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The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Abstract The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

Imaging Mass Cytometry (IMC) is a novel, and formidable high multiplexing imaging method emerging as a promising tool for in-depth studying of tissue architecture and intercellular communications. Several studies have reported various IMC antibody panels mainly focused on studying the immunological landscape of the tumor microenvironment (TME). With this paper, we wanted to address cancer associated fibroblasts (CAFs), a component of the TME very often underrepresented and not emphasized enough in present IMC studies. Therefore, we focused on the development of a comprehensive IMC panel that can be used for a thorough description of the CAF composition of breast cancer TME and for an in-depth study of different CAF niches in relation to both immune and breast cancer cell communication. We established and validated a 42 marker panel using a variety of control tissues and rigorous quantification methods. The final panel contained 6 CAF-associated markers (aSMA, FAP, PDGFRa, PDGFRb, YAP1, pSMAD2). Breast cancer tissues (4 cases of luminal, 5 cases of triple negative breast cancer) and a modified CELESTA pipelinewere used to demonstrate the utility of our IMCpanel for detailed profiling of different CAF, immune and cancer cell phenotypes. [ABSTRACT FROM AUTHOR]

Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxiainducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having antitumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To explore the predictive merit of MFAP2+ cancer associated fibroblasts (CAFs) infiltration for clinical outcomes and adjuvant chemotherapy or immunotherapy responsiveness in gastric cancer (GC). Methods: In this study, several independent cohorts were included respectively to dissect the relationship of clinical outcomes, therapeutic responses and tumor microenvironment with different MFAP2+ CAFs infiltration. Drug sensitivity analysis was conducted to predict the relationship between MFAP2+ CAFs infiltration and targeted drug response. Kaplan–Meier curves and the log-rank test were used to compare clinical outcomes of patients with different MFAP2+ CAFs infiltration. Results: High MFAP2+ CAFs infiltration yielded inferior prognosis in terms of overall survival, progress free survival and recurrence free survival in GC. Patients with low MFAP2+ CAFs infiltration were more likely to gain benefit from adjuvant therapy. Moreover, low MFAP2+ CAFs infiltration could predict a promising response to immunotherapy in GC patients. MFAP2+ CAFs with immunosuppressive features were highly relevant to immune evasive contexture characterized by the dysfunction of CD8+ T cells. We found that MFAP2+ CAFs communicated with T cells, B cells and Macrophages through releasing macrophage migration inhibitor factor (MIF), which further suggested that MFAP2+ CAFs might promote therapeutic resistance through regulating T cells dysfunction and M2 macrophages polarization. Conclusion: Immunosuppressive MFAP2+ CAFs constructed an immune evasive tumor microenvironment characterized by incapacitated immune effector cells, consequently predicting inferior clinical outcomes and response on adjuvant therapy and immunotherapy in patients with GC. The potential of immunosuppressive MFAP2+ CAFs as a therapeutic target for GC deserved thoroughly exploration. [ABSTRACT FROM AUTHOR]

Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch. [ABSTRACT FROM AUTHOR]

To decipher the interactions between various components of the tumor microenvironment (TME) and tumor cells in a preserved spatial context, a multiparametric approach is essential. In this pursuit, imaging mass cytometry (IMC) emerges as a valuable tool, capable of concurrently analyzing up to 40 parameters at subcellular resolution. In this study, a set of antibodies was selected to spatially resolve multiple cell types and TME elements, including a comprehensive panel targeted at dissecting the heterogeneity of cancer-associated fibroblasts (CAF), a pivotal TME component. This antibody panel was standardized and optimized using formalin-fixed paraffin-embedded tissue (FFPE) samples from different organs/lesions known to express the markers of interest. The final composition of the antibody panel was determined based on the performance of conjugated antibodies in both immunohistochemistry (IHC) and IMC. Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R program. This paper provides a detailed description of the staining procedure and analysis workflow. Subsequently, the panel underwent validation on clinical FFPE samples from head and neck squamous cell carcinoma (HNSCC). The panel and bioinformatics pipeline established here proved to be robust in characterizing different TME components of HNSCC while maintaining a high degree of spatial detail. The platform we describe shows promise for understanding the clinical implications of TMA heterogeneity in large patient cohorts with FFPE tissues available in diagnostic biobanks worldwide.

Imaging Mass Cytometry (IMC) is a novel, and formidable high multiplexing imaging method emerging as a promising tool for in-depth studying of tissue architecture and intercellular communications. Several studies have reported various IMC antibody panels mainly focused on studying the immunological landscape of the tumor microenvironment (TME). With this paper, we wanted to address cancer associated fibroblasts (CAFs), a component of the TME very often underrepresented and not emphasized enough in present IMC studies. Therefore, we focused on the development of a comprehensive IMC panel that can be used for a thorough description of the CAF composition of breast cancer TME and for an in-depth study of different CAF niches in relation to both immune and breast cancer cell communication. We established and validated a 42 marker panel using a variety of control tissues and rigorous quantification methods. The final panel contained 6 CAF-associated markers (aSMA, FAP, PDGFRa, PDGFRb, YAP1, pSMAD2). Breast cancer tissues (4 cases of luminal, 5 cases of triple negative breast cancer) and a modified CELESTA pipeline were used to demonstrate the utility of our IMC panel for detailed profiling of different CAF, immune and cancer cell phenotypes.

Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment‐resistant to treatment‐vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre‐oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune‐to‐essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors. [ABSTRACT FROM AUTHOR]

Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.

Cancer-associated fibroblasts (CAFs) consist of heterogeneous cellular populations that contribute critical roles in head and neck squamous cell carcinoma (HNSCC). A series of computer-aided analyses were performed to determine various aspects of CAFs in HNSCC, including their cellular heterogeneity, prognostic value, relationship with immune suppression and immunotherapeutic response, intercellular communication, and metabolic activity. The prognostic significance of CKS2+ CAFs was verified using immunohistochemistry. Our findings revealed that fibroblasts group demonstrated prognostic significance, with the CKS2+ subset of inflammatory CAFs (iCAFs) exhibiting a significant correlation with unfavorable prognosis and being localized in close proximity to cancer cells. Patients with a high infiltration of CKS2+ CAFs had a poor overall survival rate. There is a negative correlation between CKS2+ iCAFs and cytotoxic CD8+ T cells and natural killer (NK) cells, while a positive correlation was found with exhausted CD8+ T cells. Additionally, patients in Cluster 3, characterized by a high proportion of CKS2+ iCAFs, and patients in Cluster 2, characterized by a high proportion of CKS2- iCAFs and CENPF-/MYLPF- myofibroblastic CAFs (myCAFs), did not exhibit significant immunotherapeutic responses. Moreover, close interactions was confirmed to exist between cancer cells and CKS2+ iCAFs/ CENPF+ myCAFs. Furthermore, CKS2+ iCAFs demonstrated the highest level of metabolic activity. In summary, our study enhances the understanding of the heterogeneity of CAFs and provided insights into improving the efficacy of immunotherapies and prognostic accuracy for HNSCC patients.

Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamineproducing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10–15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments. [ABSTRACT FROM AUTHOR]

The cancer secretome reflects the assortment of proteins released by cancer cells. Investigating cell secretomes not only provides a deeper knowledge of the healthy and transformed state but also helps in the discovery of novel biomarkers. Secretomes of cancer cells have been studied in the past, however, the secretome contribution of stromal cells needs to be studied. Cancer-associated fibroblasts (CAFs) are one of the predominantly present cell populations in the tumor microenvironment (TME). CAFs play key role in functions associated with matrix deposition and remodeling, reciprocal exchange of nutrients, and molecular interactions and signaling with neighboring cells in the TME. Investigating CAFs secretomes or CAFs-secreted factors would help in identifying novel CAF-specific biomarkers, unique druggable targets, and an improved understanding for personalized cancer diagnosis and prognosis. In this review, we have tried to include all studies available in PubMed with the keywords "CAFs Secretome". We aim to provide a comprehensive summary of the studies investigating role of the CAF secretome on cancer development, progression, and therapeutic outcome. However, challenges associated with this process have also been addressed in the later sections. We have highlighted the functions and clinical relevance of secretome analysis in stromal CAF-rich cancer types. This review specifically discusses the secretome of stromal CAFs in cancers. A deeper understanding of the components of the CAF secretome and their interactions with cancer cells will help in the identification of personalized biomarkers and a more precise treatment plan. [ABSTRACT FROM AUTHOR]

Although the prognosis for acute leukemia has greatly improved, treatment of relapsed/refractory acute leukemia (R/R AL) remains challenging. Recently, increasing evidence indicates that the bone marrow microenvironment (BMM) plays a crucial role in leukemogenesis and therapeutic resistance; therefore, BMM-targeted strategies should be a potent protocol for treating R/R AL. The targeting of cancer-associated fibroblasts (CAFs) in solid tumors has received much attention and has achieved some progress, as CAFs might act as an organizer in the tumor microenvironment. Additionally, over the last 10 years, attention has been drawn to the role of CAFs in the BMM. In spite of certain successes in preclinical and clinical studies, the heterogeneity and plasticity of CAFs mean targeting them is a big challenge. Herein, we review the heterogeneity and roles of CAFs in the BMM and highlight the challenges and opportunities associated with acute leukemia therapies that involve the targeting of CAFs.

Systemic treatments (e.g., chemotherapy and targeted therapies) have limited efficacy for patients with locally advanced – unresectable – and metastatic cholangiocarcinoma (CCA), with an overall survival of less than a year. Tumor microenvironment (TME) represents the ecosystem surrounding the tumor which comprises immune cells, fibroblasts, endothelial cells, and a wide range of soluble factors. CCA TME is characterized by an abundant desmoplastic stroma, exhibits a high heterogeneity and it plays a central role in cancer onset and progression. There is growing evidence suggesting that it is possible to target TME in association with other treatment modalities, such as cytotoxic chemotherapy or targeted therapies, paving the way to possible combination strategies with a synergistic effect. Herein, we describe the components of CCA TME – such as cancer-associated fibroblasts and other cells of pivotal importance - with their most relevant interactions, focusing on the preclinical rationale for the development of effective anticancer treatments.

Abstract Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.

• Desmoplasia is characterized by aberrant ECM remodelling and altered CAFs function. • CAFs inhabiting PDAC TME show high functional heterogeneity and plasticity. • Hypoxia, nutrient deprivation, and CAFs affect NK cell TME penetration and activity. • Dissecting NK cell heterogeneity in tumor tissue may improve current PDAC therapies. Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent pancreatic cancer and represents one of the most aggressive human neoplasms. Typically identified at advance stage disease, most PDAC tumors are unresectable and resistant to standard therapies. The immunosuppressive microenvironment in PDAC impedes tumor control but a greater understanding of the complex stromal interactions within the tumor microenvironment (TME) and the development of strategies capable of restoring antitumor effector immune responses could be crucial to fight this aggressive tumor and its spread. Natural Killer (NK) cells play a crucial role in cancer immunosurveillance and represent an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. This review describes some crucial components of the PDAC TME (collagens, soluble factors and fibroblasts) that can influence the presence, phenotype and function of NK cells in PDAC patients tumor tissue. This focused overview highlights the therapeutic relevance of dissecting the complex stromal composition to define new strategies for NK cell-based immunotherapies to improve the treatment of PDAC. [ABSTRACT FROM AUTHOR]

[Display omitted] The role of tumor stroma in solid tumors has been widely recognized in cancer progression, metastasis and chemoresistance. Cancer-associated fibroblasts (CAFs) play a crucial role in matrix remodeling and promoting cancer cell stemness and resistance via reciprocal crosstalk. Residual tumor tissue after surgical removal as well as unresectable tumors face therapeutic challenges to achieve curable outcome. In this study, we propose to develop a dual delivery approach by combining p21-activated kinase 1 (PAK1) inhibitor (FRAX597) to inhibit tumor stroma and chemotherapeutic agent paclitaxel (PTX) to kill cancer cells using electrospun nanofibers. First, the role of the PAK1 pathway was established in CAF differentiation, migration and contraction using relevant in vitro models. Second, polycaprolactone polymer-based nanofibers were fabricated using a uniaxial electrospinning technique to incorporate FRAX597 and/or PTX, which showed a uniform texture and a prolonged release of both drugs for 16 days. To test nanofibers, stroma-rich 3D heterospheroid models were set up which showed high resistance to PTX nanofibers compared to stroma-free homospheroids. Interestingly, nanofibers containing PTX and FRAX597 showed strong anti-tumor effects on heterospheroids by reducing the growth and viability by > 90 % compared to either of single drug-loaded nanofibers. These effects were reflected by reduced intra-spheroidal expression levels of collagen 1 and α-smooth muscle actin (α-SMA). Overall, this study provides a new therapeutic strategy to inhibit the tumor stroma using PAK1 inhibitor and thereby enhance the efficacy of chemotherapy using nanofibers as a local delivery system for unresectable or residual tumor. Use of 3D models to evaluate nanofibers highlights these models as advanced in vitro tools to study the effect of controlled release local drug delivery systems before animal studies. [ABSTRACT FROM AUTHOR]

The cancer secretome reflects the assortment of proteins released by cancer cells. Investigating cell secretomes not only provides a deeper knowledge of the healthy and transformed state but also helps in the discovery of novel biomarkers. Secretomes of cancer cells have been studied in the past, however, the secretome contribution of stromal cells needs to be studied. Cancer-associated fibroblasts (CAFs) are one of the predominantly present cell populations in the tumor microenvironment (TME). CAFs play key role in functions associated with matrix deposition and remodeling, reciprocal exchange of nutrients, and molecular interactions and signaling with neighboring cells in the TME. Investigating CAFs secretomes or CAFs-secreted factors would help in identifying novel CAF-specific biomarkers, unique druggable targets, and an improved understanding for personalized cancer diagnosis and prognosis. In this review, we have tried to include all studies available in PubMed with the keywords “CAFs Secretome”. We aim to provide a comprehensive summary of the studies investigating role of the CAF secretome on cancer development, progression, and therapeutic outcome. However, challenges associated with this process have also been addressed in the later sections. We have highlighted the functions and clinical relevance of secretome analysis in stromal CAF-rich cancer types. This review specifically discusses the secretome of stromal CAFs in cancers. A deeper understanding of the components of the CAF secretome and their interactions with cancer cells will help in the identification of personalized biomarkers and a more precise treatment plan.

Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major components of the tumor microenvironment. TAMs promote tumor progression, angiogenesis and tissue remodeling. However, the impact of the molecular crosstalk of tumor cells (TCs) with CAFs and macrophages on monocyte recruitment and their phenotypic conversion is not known in detail so far. In a 3D human organotypic CRC model, we show that CAFs and normal colonic fibroblasts are critically involved in monocyte recruitment and for the establishment of a macrophage phenotype, characterized by high CD163 expression. This is in line with the steady recruitment and differentiation of monocytes to immunosuppressive macrophages in the normal colon. Cytokine profiling revealed that CAFs produce M-CSF, and IL6, IL8, HGF and CCL2 secretion was specifically induced by CAFs in co-cultures with macrophages. Moreover, macrophage/CAF/TCs co-cultures increased TC invasion. We demonstrate that CAFs and macrophages are the major producers of CCL2 and, upon co-culture, increase their CCL2 production twofold and 40-fold, respectively. CAFs and macrophages expressing high CCL2 were also found in vivo in CRC, strongly supporting our findings. CCL2, CCR2, CSF1R and CD163 expression in macrophages was dependent on active MCSFR signaling as shown by M-CSFR inhibition. These results indicate that colon fibroblasts and not TCs are the major cellular component, recruiting and dictating the fate of infiltrated monocytes towards a specific macrophage population, characterized by high CD163 expression and CCL2 production. • CAFs as well as normal fibroblasts are critically involved in the recruitment of monocytes in colon and colon cancer. • CAFs induce a specific macrophage phenotype, which is characterized by high CD163 and CCL2 expression. • CAFs and macrophages significantly increase their CCL2 production upon co-culture, whereas tumor cells do not produce CCL2. • CCL2, CCR2, M-CSFR and CD163 expression was dependent on active M-CSFR signaling in macrophages. • High CCL2 levels in CAFs/macrophages were found in vivo in human CRC by dissection, scRNA-Seq and immunofluorescence. [ABSTRACT FROM AUTHOR]

Cancer associated fibroblasts (CAFs) are the most abundant stromal cell-type in solid tumor-microenvironment (TME) and have emerged as key player in tumor progression. CAFs establish communication with cancer cells through paracrine mechanisms or via direct cell adhesion as well as influence the cancer cell behaviour indirectly by remodelling the extracellular matrix. Although numerous studies have strongly suggested the tumor promoting role of CAFs, few recent reports have revealed the heterogeneity in CAFs. Here, we have summarized the recent findings on the mechanisms related to the heterogeneous behaviour of CAFs serving as positive or negative regulator of tumor progression. Further, reports related to the targeted therapy against CAF-mediated mechanisms are also summarized briefly.

Interactions of genetic susceptibility factors, immune microenvironment, and microbial factors contribute to gastrointestinal tumorigenesis. The suppressive immune microenvironment reshaped by the tumors during gastrointestinal tumorigenesis directly contributes to T-cell depletion in tumor immunotherapy. Soluble factors secreted by tumor cells or stromal cells collectively shape the suppressive immune environment. Here, we reviewed the key factors in the gastrointestinal tumor microenvironment that influence tumor immunotherapy, focusing on the effects of fibroblasts, neuronal cells, soluble cytokines, exosomes, and the microbiome in tumor microenvironment. Research in this field has helped to identify more precise and effective biomarkers and therapeutic targets in the era of tumor immunotherapy.

Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other's functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is the eighth most common type of cancer and the sixth leading cause of cancer-related deaths worldwide. At present, the clinical treatment for EC is based mainly on radical surgery, chemotherapy, and radiotherapy. However, due to the limited efficacy of conventional treatments and the serious adverse reactions, the outcome is still unsatisfactory (the 5-year survival rate for patients is less than 25%). Thus, it is extremely important and urgent to identify new therapeutic targets. The concept of tumor microenvironment (TME) has attracted increased attention since it was proposed. Recent studies have shown that TME is an important therapeutic target for EC. Microenvironment-targeting therapies such as immunotherapy and antiangiogenic therapy have played an indispensable role in prolonging survival and improving the prognosis of patients with EC. In addition, many new drugs and therapies that have been developed to target microenvironment may become treatment options in the future. We summarize the microenvironment of EC and the latest advances in microenvironment-targeting therapies in this review.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, partly due to the dense desmoplasia and a lack of suitable model systems to study. In the present work, we developed a 3D heterospecies spheroid model to study the microenvironmental interactions between tumor cells and stellate cells which can also be employed to test therapeutic regimens. We set up monospheroids and heterospheroids made up from murine pancreatic stellate cells (mPSCs) and human PDAC cells (Panc1), which allowed for direct isolation of mRNA from a mixed cell population followed by an in silico separation of the RNA-seq reads. Global transcript level changes for cells in heterospheroids versus monospheroids were calculated, followed by gene set enrichment analysis and molecular subtype analysis. We observed an apparent shift of Panc1 from the classical to the squamous/basal-like phenotype upon co-culture with mPSCs. Moreover, mPSCs acquired a different cancer-associated fibroblast-related phenotype upon co-culture with Panc1. We analyzed the tumor cell-specific chemosensitivities towards gemcitabine, paclitaxel and SN38 and compared these to published pharmacotranscriptomic signatures. In conclusion, our heterospecies spheroid model reflected key aspects of PDAC and facilitated the study of intercellular interactions between tumor and stroma while additionally proving to be a good model for studying therapeutic responses.

Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

Background: Pancreatic ductal adenocarcinoma (PDAC) is most aggressive among all gastrointestinal tumors. The complex intra-tumor heterogeneity and special tumor microenvironment in PDAC bring great challenges for developing effective treatment strategies. We aimed to delineate dynamic changes of tumor microenvironment components during PDAC malignant progression utilizing single-cell RNA sequencing. Methods: A total of 11 samples (4 PDAC I, 4 PDAC II, 3 PDAC III) were used to construct expression matrix. After identifying distinct cell clusters, subcluster analysis for each cluster was performed. New cancer associated fibroblasts (CAFs) subset was validated by weighted gene co-expression network analysis, RNA in situ hybridization and immunofluorescence. Findings: We found that ductal cells were not dominant component while tumor infiltrating immune cells and pancreatic stellate cells gradually accumulated during tumor development. We defined several new Treg and exhausted T cell signature genes, including DUSP4, FANK1 and LAIR2. The analysis of TCGA datasets showed that patients with high expression of DUSP4 had significantly worse prognosis. In addition, we identified a new CAFs subset (complement-secreting CAFs, csCAFs), which specifically expresses complement system components, and constructed csCAFs-related module by weighted gene co-expression network analysis. The csCAFs were located in the tissue stroma adjacent to malignant ductal cells only in early PDAC. Interpretation: We systematically explored PDAC heterogeneity and identified csCAFs as a new CAFs subset special to PDAC, which may be valuable for understanding the crosstalk inside tumor. Funding: This study was supported by The Natural Science Foundation of China (NO.81572339, 81672353, 81871954) and the Youth Clinical Research Project of Peking University First Hospital (2018CR28).

Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies. [ABSTRACT FROM AUTHOR]

Years of investigation have shed light on a theory in which breast tumor epithelial cells are under the effect of the stromal microenvironment. This review aims to discuss recent findings concerning the phenotypic and functional characteristics of cancer associated fibroblasts (CAFs) and their involvement in tumor evolution, as well as their potential implications for anti-cancer therapy. In this manuscript, we reviewed that CAFs play a fundamental role in initiation, growth, invasion, and metastasis of breast cancer, and also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of this disease. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA), the malignant tumor of bile duct epithelial cells, is a relatively rare yet highly lethal cancer. In this work, we tested the ability of Resveratrol (RV) to prevent and cure CCA xenograft in nude mice and investigated molecular mechanisms underpinning such anticancer effect. Human CCA cells were xenografted in mice that were or not treated prior to or after to transplantation with RV. Tumor growth was monitored and analyzed for the markers of cell proliferation, apoptosis, and autophagy. TCGA was interrogated for the molecules possibly targeted by RV. RV could inhibit the growth of human CCA xenograft when administered after implantation and could reduce the growth or even impair the implantation of the tumors when administered prior the transplantation. RV inhibited CCA cell proliferation, induced apoptosis with autophagy, and strongly reduced the presence of CAFs and production of IL-6. Interrogation of CCA dataset in TCGA database revealed that the expression of IL-6 Receptor (IL-6R) inversely correlated with that of MAP-LC3 and BECLIN-1 , and that low expression of IL-6R and of MIK67 , two pathways downregulated by RV, associated with better survival of CCA patients. Our data demonstrate that RV elicits a strong preventive and curative anticancer effect in CCA by limiting the formation of CAFs and their release of IL-6, and this results in up-regulation of autophagy and apoptosis in the cancer cells. These findings support the clinical use of RV as a primary line of prevention in patients exposed at risk and as an adjuvant therapeutics in CCA patients. • Interleukin-6 (IL-6), released by cancer associated fibroblasts (CAFs), plays a pivotal role in cholangiocarcinoma (CCA) progression, driving chemoresistance. • CAFs-derived IL-6 stimulates CCA progression via down-regulates autophagy. • Resveratrol (RV) strongly reduces the stromal content of CAFs and IL-6. • RV inhibits the growth of xenograft CCA in nude mice through induction of autophagy and apoptosis. • RV treatment decreases the expression of IL-6, BCL-2 and Ki-67, while increases that of p21, LC3 and BECLIN-1. [ABSTRACT FROM AUTHOR]

Abstract Immune checkpoint inhibitor therapy has changed clinical practice for patients with different cancers, since these agents have demonstrated a significant improvement of overall survival and are effective in many patients. However, an intrinsic or acquired resistance frequently occur and biomarkers predictive of responsiveness should help in patient selection and in defining the adequate treatment options. A deep analysis of the complexity of the tumor microenvironment is likely to further advance the field and hopefully identify more effective combined immunotherapeutic strategies. Here we review the current knowledge on tumor microenvironment, focusing on T cells, cancer associated fibroblasts and extracellular matrix. The use of 3D cell culture models to resemble tumor microenvironment landscape and to screen immunomodulatory drugs is also reviewed.

Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment. [ABSTRACT FROM AUTHOR]

Background/Aims: The malignant biological behavior of gastric cancer(GC) is not only determined by cancer cells alone, but also closely regulated by the microenvironment. Fibroblasts represent a large proportion of the components in the tumor microenvironment, and they promote the development of disease. Currently, accumulating evidence suggests that exosomes can function as intercellular transport systems to relay their contents, especially microRNAs(miRNAs). Methods: First, we detected the highly-expressed level of miR-27a in exosomes isolated from gastric cancer cells by qRT-PCR. MiR-27a –over-expressed models in vitro and in vivo were established to investigate the transformation of cancer-associated fibroblasts observed by Western blotting, and the malignant behavior of gastric cancer cells using the methods CCK8 and Transwell. Moreover, the downregulation of CSRP2 in fibroblasts was used to evaluate the promotion of malignancy of gastric cancer using the methods CCK8 and Transwell. Results: In this study, we found a marked high level of miR-27a in exosomes derived from GC cells. miR-27a was found to function an oncogene that not only induced the reprogramming of fibroblasts into cancer-associated fibroblasts(CAFs), but also promoted the proliferation, motility and metastasis of cancer cells in vitro and in vivo. Conversely, CAFs with over-expression of miR-27a could pleiotropically increase the malignant behavior of the GC cells. For the first time, we revealed that CSRP2 is a downstream target of miR-27a. CSRP2 downregulation could increase the proliferation and motility of GC cells. Conclusion: Thus, this report indicates that miR-27a in exosomes derived from GC cells has a crucial impact on the microenvironment and may be used as a potential therapeutic target in the treatment of GC

The extracellular matrix (ECM) is a complex network of secreted proteins which provides support for tissues and organs. Additionally, the ECM controls a plethora of cell functions, including cell polarity, migration, proliferation, and oncogenic transformation. One of the hallmarks of cancer is altered cell metabolism, which is currently being exploited to develop anti-cancer therapies. Several pieces of evidence indicate that the tumor microenvironment and the ECM impinge on tumor cell metabolism. Therefore, it is essential to understand the contribution of the complex 3D microenvironment in controlling metabolic plasticity and responsiveness to therapies targeting cell metabolism. In this mini-review, we will describe how the tumor microenvironment and cancer-associated fibroblasts dictate cancer cell metabolism, resulting in increased tumor progression. Moreover, we will define the cross-talk between nutrient signaling and the trafficking of the ECM receptors of the integrin family. Finally, we will present recent data highlighting the contribution of nutrient scavenging from the microenvironment to support cancer cells growth under nutrient starvation conditions. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen‐binding integrin α11β1 has been proposed to be upregulated in a pro‐tumorigenic subtype of cancer‐associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin α11β1 in a large breast cancer series using a novel antibody against the human integrin α11 chain. Several novel monoclonal antibodies against the integrin α11 subunit were tested for use on formalin‐fixed paraffin‐embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co‐expression patterns of integrin α11 in relation to αSMA and cytokeratin‐14 were also investigated. Integrin α11 was expressed to varying degrees in spindle‐shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin α11 co‐localized with αSMA in stromal cells, and with αSMA and cytokeratin‐14 in breast myoepithelium. High stromal integrin α11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple‐negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin α11 expression was associated with aggressive breast cancer phenotypes. [ABSTRACT FROM AUTHOR]

In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma.

Purpose: Previous analyses of the tumor microenvironment (TME) have resulted in a concept that tumor progression may depend on interactions between cancer cells and its surrounding stroma. An important aspect of these interactions is the ability of cancer cells to modulate stroma behavior, and vice versa, through the action of a variety of soluble mediators. Here, we aimed to identify soluble factors present in the TME of colorectal cancer cells that may affect relevant pathways through secretome profiling. Methods: To partially recapitulate the TME and its architecture, we co-cultured colorectal cancer cells (SW480, TC) with stromal fibroblasts (MRC-5, F) as 3D-spheroids. Subsequent characterization of both homotypic (TC) and heterotypic (TC + F) spheroid secretomes was performed using label-free liquid chromatography-mass spectrometry (LC-MS). Results: Through bioinformatic analysis using the NCI-Pathway Interaction Database (NCI-PID) we found that the HIF-1 signaling pathway was most highly enriched among the proteins whose secretion was enhanced in the heterotypic spheroids. Previously, we found that HIF-1 may be associated with resistance of colorectal cancer cells to photodynamic therapy (PDT), an antitumor therapy that combines photosensitizing agents, O2 and light to create a harmful photochemical reaction. Here, we found that the presence of fibroblasts considerably diminished the sensitivity of colorectal cancer cells to photodynamic activity. Although the biological significance of the HIF-1 pathway of secretomes was decreased after photosensitization, this decrease was partially reversed in heterotypic 3D-spheroids. HIF-1 pathway modulation by both PDT and stromal fibroblasts was confirmed through expression assessment of the HIF-target VEGF, as well as through HIF transcriptional activity assessment. Conclusion: Collectively, our results delineate a potential mechanism by which stromal fibroblasts may enhance colorectal cancer cell survival and photodynamic treatment resistance via HIF-1 pathway modulation. [ABSTRACT FROM AUTHOR]

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support tumor growth, generating a physical barrier against drugs and immune infiltration, and contributing to regulate malignant progression. Thus, it is largely accepted that therapeutic approaches aimed at hampering the interactions between tumor cells and CAFs can enhance the effectiveness of anti-cancer treatments. In this view, nucleic acid therapeutics have emerged as promising molecules. Here, we summarize recent knowledge about their role in the regulation of CAF transformation and tumor-promoting functions, highlighting their therapeutic utility and challenges.

Metabolic programs are rewired in tumors to support growth, progression, and immune evasion. A wealth of work in the past decade has delineated how these metabolic rearrangements are facilitated by signaling pathways downstream of oncogene activation and tumor suppressor loss. More recently, this field has expanded to include metabolic interactions among the diverse cell types that exist within a tumor and how this impacts the immune system. In this special issue, 17 review articles discuss these phenomena, and, alongside four original research manuscripts, the vulnerabilities associated with deregulated metabolic programming are highlighted and examined.

Gastrointestinal cancers (GI), are a group of highly aggressive malignancies with heavy cancer‐related mortalities. Even if continued development of therapy methods, therapy resistance has been a great obstruction for cancer treatment and thereby inevitably leads to depressed final mortality. Peritumoral cancer associated fibroblasts (CAFs), a versatile population assisting cancer cells to build a facilitated tumor microenvironment (TME), has been demonstrated exerting a promotion influence on cancer proliferation, migration, invasion, metastasis, and also therapy resistance. In this review, we provide an update progress in describing how CAFs mediate therapy resistance in GI by various means, meanwhile highlight the crosstalk between CAFs and cancer cells and present some vital signaling pathways activated by CAFs in this resistant process. Furthermore, we discuss the current advances in adopting novel drugs against CAFs and how the knowledge contributing to improved therapy efficacy in clinical practice. In sum, CAFs create a therapy‐resistant TME in several aspects of GI progression, although some key problems about distinguishing CAFs subpopulations and controversial issues on pleiotropic CAFs in medication need to be solved for subsequent clinical application. Predictably, targeting therapy‐resistant CAFs is a promising adjunctive treatment to benefit GI patients. [ABSTRACT FROM AUTHOR]

It has become clear that non-tumor cells in the microenvironment, especially fibroblasts, actively participate in tumor progression. Fibroblasts conditioned by tumor cells become “activated” and, as such, are identified as CAFs (cancer-associated fibroblasts). These CAFs remodel the tumor stroma to make it more favourable for cancer progression. The aim of this work was to verify whether EVs (extracellular vesicles - whose role as mediators of information between tumor and stromal cells is well known) released from human ovarian cancer cells were able to activate fibroblasts. EVs isolated from SKOV3 (more aggressive) and CABA I (less aggressive) cells were administered to fibroblasts. The consequent activation was supported by morphological and molecular changes in treated fibroblasts; XTT assays, zymographies, wound healing tests and invasion assays also highlighted higher proliferation, motility, invasiveness and enzyme expression. The secretome of these “activated” fibroblasts was, in turn, able to modulate the responses (proliferation, motility and invasion) of fibroblasts, and of tumor and endothelial cells. These findings support the idea that ovarian cancer cells can modulate fibroblast behaviour through the release of EVs, activating them to a CAFs-like state; the latter are able, in turn, to stimulate the surrounding cells. EVs from SKOV3 rather than from CABA I seem to be more efficient in some processes. [ABSTRACT FROM AUTHOR]

The novelty of an effective therapeutic targeting for hepatocellular carcinoma (HCC) is based on improved understanding of each component of tumor microenvironment (TME) and its correspondent interactions at biological and molecular levels. In this context, new expansions for the treatment against TME and its communication with HCC are under exploration. Despite of the fact that blockage of growth factor receptors has become a treatment of choice in late phases of HCC in clinical practice, still a precise targeted treatment should address all the components of TME. Targeting one specific element out of cellular (cancer associated fibroblasts, endothelial cells, hepatic stellate cells, Kupffer cells and lymphocytes) or non-cellular (extracellular matrix, growth factors, inflammatory cytokines, proteolytic enzymes) parts of TME may not be a successful remedy for the disease because of well-designed hindrances of each component and their functional alternativeness. Meanwhile there are some elements of TME like epithelial-mesenchymal transition and CAF, which are considerably important and need thorough investigations. Ascertaining the potential role of these elements, and a single or combinational drug therapy targeting these elements of TME simultaneously, may provide the appreciable considerations to eventually improve in clinical practices and may also minimize the chances of reoccurrence of HCC. [ABSTRACT FROM AUTHOR]

Background: The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression. Results: Cancer dynamics are explored using a model involving genes mediating the regulatory interactions between the signaling and metabolic pathways. The exploration is informed by a proposed genetic dysregulation measure of cellular processes. The analysis of the interaction dynamics between cancer cells, cancer associated fibroblasts, and tumor associate macrophages suggests that the mutual dependence of these cells promotes cancer growth and proliferation. In particular, MTOR and AMPK are hypothesized to be concurrently activated in cancer cells by amino acids recycled from the stroma. This leads to a proliferative growth supported by an upregulated glycolysis and a tricarboxylic acid cycle driven by glutamine sourced from the stroma. In other words, while genetic aberrations ignite carcinogenesis and lead to the dysregulation of key cellular processes, it is postulated that the dysregulation of metabolism locks cancer cells in a state of mutual dependence with the tumor microenvironment and deepens the tumor's inflammation and immunosuppressive state which perpetuates as a result the growth and proliferation dynamics of cancer. Conclusions: Cancer therapies should aim for a progressive disruption of the dynamics of interactions between cancer cells and the tumor microenvironment by targeting metabolic dysregulation and inflammation to partially restore tissue homeostasis and turn on the immune cancer kill switch. One potentially effective cancer therapeutic strategy is to induce the reduction of lactate and steer the tumor microenvironment to a state of reduced inflammation so as to enable an effective intervention of the immune system. The translation of this therapeutic approach into treatment regimens would however require more understanding of the adaptive complexity of cancer resulting from the interactions of cancer cells with the tumor microenvironment and the immune system. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) exert various effects upon biological behaviours of cancer. In this study, we examined the correlation of CAFs with the intra-tumoural immune system in the lung adenocarcinoma microenvironment. We studied 27 and 113 cases of lung adenocarcinoma tentatively as Cohorts 1 and 2, respectively. The patients in Cohort 1 received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for recurrent lung adenocarcinoma. α-smooth muscle actin (α-SMA), a surrogate marker for CAFs, was examined by immunohistochemistry. We then examined the effects of CAFs isolated from lung cancer tissues on programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma cell lines. No significant associations were detected between α-SMA status and the ratios of CD8/CD4 and Foxp3/CD8 in Cohort 1. However, α-SMA status was significantly associated with PD-L1 status in both Cohorts 1 and 2. Conditioned medium of CAFs significantly induced PD-L1 expression in lung adenocarcinoma cell lines, A549, PC-9, and H1975. Among the cytokines examined by antibody array, C-X-C motif chemokine ligand 2 (CXCL2) increased PD-L1 mRNA expression in these cell lines. CXCL2 is therefore considered to have a potential to induce PD-L1 expression in lung adenocarcinoma cells as a result of an interaction between carcinoma cells and CAFs. These findings did firstly demonstrate that CAFs indirectly influenced tumour immunity through increasing PD-L1 expression in lung adenocarcinoma cells.

Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10⁻60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This review will describe the various hypotheses about the origin of CAFs, their major functions in the tumor microenvironment in ovarian cancer, and will discuss the potential of targeting CAFs as a possible therapeutic approach.