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Background: The Apoptosis-Stimulating Protein of P53 (ASPP) family contributes to apoptosis regulation and tumor suppression, with ASPP1 influencing processes like cancer cell proliferation, invasion, and migration. Its expression varies across cancer types, suggesting a potential role in oncogenesis. Methods: This study investigates ASPP1's role across various cancers using a comprehensive bioinformatics approach. Data were extracted from public resources, including The Cancer Genome Atlas (TCGA), GTEx, and the Human Protein Atlas, and analyzed via tools such as cBioPortal, GEPIA, and TIMER2. Statistical and network analyses were performed with R, Cytoscape, and Hiplot. ASPP1's function in colorectal cancer was further explored through in vitro assays, including qRT-PCR, Western blotting, colony formation, Transwell, and wound healing. Results: ASPP1 expression exhibited significant variability across different cancer types, with marked associations with patient outcomes, particularly overall survival (OS) and disease-specific survival (DSS) across several cancer types. In-depth protein-protein interaction (PPI) analysis revealed ASPP1's involvement in apoptosis and cancer progression networks. Functional enrichment analysis further linked ASPP1 to key apoptotic signaling pathways and transcriptional regulatory processes, underscoring its potential impact on tumor biology. Additionally, the expression of ASPP1 correlates with immune cell infiltration patterns, including cancer-associated fibroblasts and various immune markers, suggesting roles in immune response modulation. In vitro assays with colorectal cancer cell lines revealed significantly lower ASPP1 expression levels compared to normal colon cells (HCM460), and ASPP1 overexpression experiments showed a marked reduction in colorectal cancer cell proliferation, colony formation, invasion, and migration abilities. These cellular findings align with the bioinformatics predictions, highlighting ASPP1's role as a suppressor of metastatic traits in colorectal cancer. Conclusion: This study highlights ASPP1 as a forecasting biomarker in the colorectal cancers and potentially across other cancers. The findings support ASPP1's involvement in tumor biology, particularly regarding cell proliferation and metastatic potential, establishing a foundation for further investigation into its therapeutic relevance. [ABSTRACT FROM AUTHOR]

BackgroundThe Apoptosis-Stimulating Protein of P53 (ASPP) family contributes to apoptosis regulation and tumor suppression, with ASPP1 influencing processes like cancer cell proliferation, invasion, and migration. Its expression varies across cancer types, suggesting a potential role in oncogenesis.MethodsThis study investigates ASPP1’s role across various cancers using a comprehensive bioinformatics approach. Data were extracted from public resources, including The Cancer Genome Atlas (TCGA), GTEx, and the Human Protein Atlas, and analyzed via tools such as cBioPortal, GEPIA, and TIMER2. Statistical and network analyses were performed with R, Cytoscape, and Hiplot. ASPP1’s function in colorectal cancer was further explored through in vitro assays, including qRT-PCR, Western blotting, colony formation, Transwell, and wound healing.ResultsASPP1 expression exhibited significant variability across different cancer types, with marked associations with patient outcomes, particularly overall survival (OS) and disease-specific survival (DSS) across several cancer types. In-depth protein-protein interaction (PPI) analysis revealed ASPP1’s involvement in apoptosis and cancer progression networks. Functional enrichment analysis further linked ASPP1 to key apoptotic signaling pathways and transcriptional regulatory processes, underscoring its potential impact on tumor biology. Additionally, the expression of ASPP1 correlates with immune cell infiltration patterns, including cancer-associated fibroblasts and various immune markers, suggesting roles in immune response modulation. In vitro assays with colorectal cancer cell lines revealed significantly lower ASPP1 expression levels compared to normal colon cells (HCM460), and ASPP1 overexpression experiments showed a marked reduction in colorectal cancer cell proliferation, colony formation, invasion, and migration abilities. These cellular findings align with the bioinformatics predictions, highlighting ASPP1’s role as a suppressor of metastatic traits in colorectal cancer.ConclusionThis study highlights ASPP1 as a forecasting biomarker in the colorectal cancers and potentially across other cancers. The findings support ASPP1’s involvement in tumor biology, particularly regarding cell proliferation and metastatic potential, establishing a foundation for further investigation into its therapeutic relevance.

The tumor microenvironment is a complex ecosystem where various cellular and molecular interactions shape the course of cancer progression. Macrophage colony-stimulating factor (M-CSF) plays a pivotal role in this context. This study delves into the biological properties and functions of M-CSF in regulating tumorassociated macrophages (TAMs) and its role in modulating host immune responses. Through the specific binding to its receptor colony-stimulating factor 1 receptor (CSF-1R), M-CSF orchestrates a cascade of downstream signaling pathways to modulate macrophage activation, polarization, and proliferation. Furthermore, M-CSF extends its influence to other immune cell populations, including dendritic cells. Notably, the heightened expression of MCSF within the tumor microenvironment is often associated with dismal patient prognoses. Therefore, a comprehensive investigation into the roles of M-CSF in tumor growth advances our comprehension of tumor development mechanisms and unveils promising novel strategies and approaches for cancer treatment. [ABSTRACT FROM AUTHOR]

Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs), stromal-derived factor-1 (SDF-1), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-b) and angiopoietins (ANGs). Accumulating evidence indicates that the role of AGFs is not only limited to tumor angiogenesis but also participating in tumor progression by other mechanisms that go beyond their angiogenic role. AGFs were shown to be upregulated in the glioma microenvironment characterized by extensive angiogenesis and high immunosuppression. AGFs produced by tumor and stromal cells can exert an immunomodulatory role in the glioma microenvironment by interacting with immune cells. This review aims to sum up the interactions among AGFs, immune cells and cancer cells with a particular emphasis on glioma and tries to provide new perspectives for understanding the glioma immune microenvironment and in-depth explorations for antiglioma therapy. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the fifth most common neoplasm and the third most deadly cancer in humans worldwide. Helicobacter pylori infection is the most important causative factor of gastric carcinogenesis, and activates host innate and adaptive immune responses. As key constituents of the tumor immune microenvironment, plasmacytoid dendritic cells (pDCs) are increasingly attracting attention owing to their potential roles in immunosuppression. We recently reported that pDCs have vital roles in the development of immunosuppression in GC. Clarifying the contribution of pDCs to the development and progression of GC may lead to improvements in cancer therapy. In this review, we summarize current knowledge regarding immune modulation in GC, especially the roles of pDCs in GC carcinogenesis and treatment strategies.

Gastric cancer (GC) is the fifth most common neoplasm and the third most deadly cancer in humans worldwide. Helicobacter pylori infection is the most important causative factor of gastric carcinogenesis, and activates host innate and adaptive immune responses. As key constituents of the tumor immune microenvironment, plasmacytoid dendritic cells (pDCs) are increasingly attracting attention owing to their potential roles in immunosuppression. We recently reported that pDCs have vital roles in the development of immunosuppression in GC. Clarifying the contribution of pDCs to the development and progression of GC may lead to improvements in cancer therapy. In this review, we summarize current knowledge regarding immune modulation in GC, especially the roles of pDCs in GC carcinogenesis and treatment strategies. [ABSTRACT FROM AUTHOR]

The Hippo pathway regulates cancer biology in many aspects and the crosstalk with other pathways complicates its role. Accumulated evidence has shown that the bidirectional interactions between tumor cells and tumor microenvironment (TME) are the premises of tumor occurrence, development, and metastasis. The relationship among different components of the TME constitutes a three-dimensional network. We point out the core position of the Hippo pathway in this network and discuss how the regulatory inputs cause the chain reaction of the network. We also discuss the important role of Hippo-TME involvement in cancer treatment.

The Hippo pathway regulates cancer biology in many aspects and the crosstalk with other pathways complicates its role. Accumulated evidence has shown that the bidirectional interactions between tumor cells and tumor microenvironment (TME) are the premises of tumor occurrence, development, and metastasis. The relationship among different components of the TME constitutes a three-dimensional network. We point out the core position of the Hippo pathway in this network and discuss how the regulatory inputs cause the chain reaction of the network. We also discuss the important role of Hippo-TME involvement in cancer treatment. [ABSTRACT FROM AUTHOR]

Several lines of clinical and experimental evidence suggest that immune cell plasticity is a central player in tumorigenesis, tumor progression, and metastasis formation. Neutrophils are able to promote or inhibit tumor growth. Through their interaction with tumor cells or their crosstalk with other immune cell subsets in the tumor microenvironment, they modulate tumor cell survival. Here, we summarize current knowledge with regards to the mechanisms that underlie neutrophil–mediated effects on tumor establishment and metastasis development. We also discuss the tumor-mediated effects on granulopoiesis and neutrophil precursors in the bone marrow and the involvement of neutrophils in anti-tumor therapeutic modalities.

Several lines of clinical and experimental evidence suggest that immune cell plasticity is a central player in tumorigenesis, tumor progression, and metastasis formation. Neutrophils are able to promote or inhibit tumor growth. Through their interaction with tumor cells or their crosstalk with other immune cell subsets in the tumor microenvironment, they modulate tumor cell survival. Here, we summarize current knowledge with regards to the mechanisms that underlie neutrophil–mediated effects on tumor establishment and metastasis development. We also discuss the tumor-mediated effects on granulopoiesis and neutrophil precursors in the bone marrow and the involvement of neutrophils in anti-tumor therapeutic modalities. [ABSTRACT FROM AUTHOR]

The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB.

The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyteassociated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB. [ABSTRACT FROM AUTHOR]

Preclinical work in murine models suggests that local radiotherapy plus intratumoral syngeneic DC injection can mediate immunologic tumor eradication. Radiotherapy affects the immune response to cancer, besides the direct impact on the tumor cells, and other ways to coordinate immune modulation with radiotherapy have been explored. We review here the potential for immune mediated anticancer activity of radiation on tumors. This is mediated by antigen acquisition and presentation by dendritic cells, and through changes of lymphocytes’ activity. Recent work has implemented the combination of external beam radiation (EBRT) with intratumoral injection of dendritic cells (DC). This included a pilot study of coordinated intraprostatic, autologous DC injection together with radiation therapy with five HLA-A2(+) subjects with high-risk, localized prostate cancer; the protocol used androgen suppression, external beam radiation therapy (25 fractions, 45 Gy), DC injections after fractions 5, 15, and 25, and then interstitial radioactive implant. Another was a phase II trial using neo-adjuvant cell death-inducing EBRT plus intra-tumoral DC in soft tissue sarcoma, to test if this would increase immune activity toward soft tissue sarcoma associated antigens. Clinical experience using radiation therapies combined with other systemic immune treatments are additionally surveyed, including use of investigational recombinant vaccinia and fowlpox, interleukin-2, toll like receptor 9 (TLR9) agonists and lymphocyte checkpoint inhibitors directed at PD1 and at CTLA4.

Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degenerative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. During the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 - 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice.

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

Preclinical work in murine models suggests that local radiotherapy plus intratumoral syngeneic dendritic cells (DC) injection can mediate immunologic tumor eradication. Radiotherapy affects the immune response to cancer, besides the direct impact on the tumor cells, and other ways to coordinate immune modulation with radiotherapy have been explored. We review here the potential for immune-mediated anticancer activity of radiation on tumors. This can be mediated by differential antigen acquisition and presentation by DC, through changes of lymphocytes' activation, and changes of tumor susceptibility to immune clearance. Recent work has implemented the combination of external beam radiation therapy (EBRT) with intratumoral injection of DC. This included a pilot study of coordinated intraprostatic, autologous DC injection together with radiation therapy with five HLA-A2(+) subjects with high-risk, localized prostate cancer; the protocol used androgen suppression, EBRT (25 fractions, 45 Gy), DC injections after fractions 5, 15, and 25, and then interstitial radioactive implant. Another was a phase II trial using neo-adjuvant apoptosis-inducing EBRT plus intra-tumoral DC in soft tissue sarcoma, to test if this would increase immune activity toward soft tissue sarcoma associated antigens. In the future, radiation therapy approaches designed to optimize immune stimulation at the level of DC, lymphocytes, tumor and stroma effects could be evaluated specifically in clinical trials. [ABSTRACT FROM AUTHOR]

Inflammatory diseases are the result of complex and pathologically unbalanced multicel-lular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degen-erative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. Dur-ing the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction, and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 and 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity.We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses.They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation.We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells. [ABSTRACT FROM AUTHOR]