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Simple Summary: Hsp90 is a protein that is often found in high levels inside cancer cells, helping them grow and spread. Yet, it is difficult to target with treatments because it's involved in many important normal cell functions. However, a subset of this population found outside the cells specifically cancer cells, called extracellular Heat-shock protein 90 (eHsp90), could be a better target for cancer therapy. eHsp90 plays a key role in helping cancer spread systemically by affecting the environment around the tumor, especially the extracellular matrix (ECM). eHsp90 changes the amount, nature and architecture of the ECM that surrounds the tumor and helps it spread locally within the tissue, which is a crucial step before ultimately metastasizing to other tissues as shown in mice models. Thus, targeting eHsp90 could help stop tumors from spreading by disrupting these processes. Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer progression. Due to the reliance of cancer cells on Hsp90's chaperone function to sustain tumor growth and spread, Hsp90 inhibitors have been the subject of numerous clinical trials over the past two decades. However, these efforts have largely been unsuccessful, primarily due to the cellular toxicity caused by pan-Hsp90 inhibitors at doses required for anticancer efficacy. Therefore, novel approaches to target Hsp90 are necessary. An identified subpopulation of Hsp90 located outside cells (eHsp90) may offer a promising alternative as a therapeutic target against cancer. Studies including our own have shown that eHsp90 is released specifically by cancer cells, and eHsp90 has unique interactors and functions extracellularly to promote tumor invasiveness, the initial step in metastasis. Inhibition of eHsp90 has been shown to suppress metastasis in animal models, indicating its therapeutic potential, although the underlying mechanisms remain incompletely understood. Cancer cells modulate the tumor microenvironment (TME) during the invasion, especially the ECM proteins and the state of the ECM is a strong predictor of invasive and metastatic cancer. Given that most of the known eHsp90 clients are ECM proteins or are proteins involved in ECM modulation, ECM remodelling could be the key mechanism through which eHsp90 enhances invasiveness. This review will focus on ECM modulation by eHsp90 as a driver of cancer invasion and metastasis. We will also discuss the potency of inhibiting eHsp90 in inhibiting invasion and metastatic spread in preclinical models and the using circulating Hsp90 patient samples as a biomarker of cancer invasion and metastasis. [ABSTRACT FROM AUTHOR]

Abstract Background Tumor cells have the ability to invade and form small clusters that protrude into adjacent tissues, a phenomenon that is frequently observed at the periphery of a tumor as it expands into healthy tissues. The presence of these clusters is linked to poor prognosis and has proven challenging to treat using conventional therapies. We previously reported that p60AmotL2 expression is localized to invasive colon and breast cancer cells. In vitro, p60AmotL2 promotes epithelial cell invasion by negatively impacting E-cadherin/AmotL2-related mechanotransduction. Methods Using epithelial cells transfected with inducible p60AmotL2, we employed a phenotypic drug screening approach to find compounds that specifically target invasive cells. The phenotypic screen was performed by treating cells for 72 h with a library of compounds with known antitumor activities in a dose-dependent manner. After assessing cell viability using CellTiter-Glo, drug sensitivity scores for each compound were calculated. Candidate hit compounds with a higher drug sensitivity score for p60AmotL2-expressing cells were then validated on lung and colon cell models, both in 2D and in 3D, and on colon cancer patient-derived organoids. Nascent RNA sequencing was performed after BET inhibition to analyse BET-dependent pathways in p60AmotL2-expressing cells. Results We identified 60 compounds that selectively targeted p60AmotL2-expressing cells. Intriguingly, these compounds were classified into two major categories: Epidermal Growth Factor Receptor (EGFR) inhibitors and Bromodomain and Extra-Terminal motif (BET) inhibitors. The latter consistently demonstrated antitumor activity in human cancer cell models, as well as in organoids derived from colon cancer patients. BET inhibition led to a shift towards the upregulation of pro-apoptotic pathways specifically in p60AmotL2-expressing cells. Conclusions BET inhibitors specifically target p60AmotL2-expressing invasive cancer cells, likely by exploiting differences in chromatin accessibility, leading to cell death. Additionally, our findings support the use of this phenotypic strategy to discover novel compounds that can exploit vulnerabilities and specifically target invasive cancer cells.

Background: Tumor cells have the ability to invade and form small clusters that protrude into adjacent tissues, a phenomenon that is frequently observed at the periphery of a tumor as it expands into healthy tissues. The presence of these clusters is linked to poor prognosis and has proven challenging to treat using conventional therapies. We previously reported that p60AmotL2 expression is localized to invasive colon and breast cancer cells. In vitro, p60AmotL2 promotes epithelial cell invasion by negatively impacting E-cadherin/AmotL2-related mechanotransduction. Methods: Using epithelial cells transfected with inducible p60AmotL2, we employed a phenotypic drug screening approach to find compounds that specifically target invasive cells. The phenotypic screen was performed by treating cells for 72 h with a library of compounds with known antitumor activities in a dose-dependent manner. After assessing cell viability using CellTiter-Glo, drug sensitivity scores for each compound were calculated. Candidate hit compounds with a higher drug sensitivity score for p60AmotL2-expressing cells were then validated on lung and colon cell models, both in 2D and in 3D, and on colon cancer patient-derived organoids. Nascent RNA sequencing was performed after BET inhibition to analyse BET-dependent pathways in p60AmotL2-expressing cells. Results: We identified 60 compounds that selectively targeted p60AmotL2-expressing cells. Intriguingly, these compounds were classified into two major categories: Epidermal Growth Factor Receptor (EGFR) inhibitors and Bromodomain and Extra-Terminal motif (BET) inhibitors. The latter consistently demonstrated antitumor activity in human cancer cell models, as well as in organoids derived from colon cancer patients. BET inhibition led to a shift towards the upregulation of pro-apoptotic pathways specifically in p60AmotL2-expressing cells. Conclusions: BET inhibitors specifically target p60AmotL2-expressing invasive cancer cells, likely by exploiting differences in chromatin accessibility, leading to cell death. Additionally, our findings support the use of this phenotypic strategy to discover novel compounds that can exploit vulnerabilities and specifically target invasive cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer cells secrete Hsp90, a protein that, inside of cells, regulates the function of hundreds of proteins, but outside of cells, extracellular Hsp90 (eHsp90) can activate a subset of proteins that promote invasion, the first step of metastasis. Blocking eHsp90 in mouse models inhibits metastasis, and we sought to understand how this occurs. Prior studies have predominantly focused on eHsp90 in cancer invasion within the immediate vicinity of the primary tumor, specifically its role in invading outside the epithelial compartment. However, eHsp90's role in cancer invasion across the extended connective tissue after the cells have crossed the boundary of the epithelial compartment remains unknown. We show here that eHsp90 directly binds to and aligns Collagen-1 fibers, a major structural component of connective tissues, which, when aligned, form highways that allow efficient cancer migration. Our study suggests that the Hsp90 dimer, in its open state, binds to Collagen-1 molecules to align the fibers, which results in enhanced breast cancer invasion through the Collagen-1 matrix. Knowing this could help us propose experiments to test eHsp90 inhibitors for therapeutically targeting metastatic breast cancer. Cancer cell-secreted eHsp90 binds and activates proteins in the tumor microenvironment crucial in cancer invasion. Therefore, targeting eHsp90 could inhibit invasion, preventing metastasis—the leading cause of cancer-related mortality. Previous eHsp90 studies have solely focused on its role in cancer invasion through the 2D basement membrane (BM), a form of extracellular matrix (ECM) that lines the epithelial compartment. However, its role in cancer invasion through the 3D Interstitial Matrix (IM), an ECM beyond the BM, remains unexplored. Using a Collagen-1 binding assay and second harmonic generation (SHG) imaging, we demonstrate that eHsp90 directly binds and aligns Collagen-1 fibers, the primary component of IM. Furthermore, we show that eHsp90 enhances Collagen-1 invasion of breast cancer cells in the Transwell assay. Using Hsp90 conformation mutants and inhibitors, we established that the Hsp90 dimer binds to Collagen-1 via its N-domain. We also demonstrated that while Collagen-1 binding and alignment are not influenced by Hsp90's ATPase activity attributed to the N-domain, its open conformation is crucial for increasing Collagen-1 alignment and promoting breast cancer cell invasion. These findings unveil a novel role for eHsp90 in invasion through the IM and offer valuable mechanistic insights into potential therapeutic approaches for inhibiting Hsp90 to suppress invasion and metastasis. [ABSTRACT FROM AUTHOR]

The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining cell–cell contacts. Furthermore, the inactivation of E-cadherin triggers invasion in vitro. However, the role of E-cadherin is complex, as metastasizing cells maintain E-cadherin expression, which appears to have a positive role in the survival of tumor cells. In this report, we present a novel mechanism delineating how E-cadherin function is modulated to promote invasion. We have previously shown that E-cadherin is associated with p100AmotL2, which is required for radial actin formation and the transmission of mechanical force. Here, we present evidence that p60AmotL2, which is expressed in invading tumor cells, binds to the p100AmotL2 isoform and uncouples the mechanical constraint of radial actin filaments. We show for the first time that the coupling of E-cadherin to the actin cytoskeleton via p100AmotL2 is directly connected to the nuclear membrane. The expression of p60AmotL2 inactivates this connection and alters the properties of the nuclear lamina, potentiating the invasion of cells into micropores of the extracellular matrix. In summary, we propose that the balance of the two AmotL2 isoforms is important in the modulation of E-cadherin function and that an imbalance of this axis promotes ameboid cell invasion. [ABSTRACT FROM AUTHOR]

The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.

Cancer is responsible for more than 10 million deaths every year. Metastasis and drug resistance lead to a poor survival rate and are a major therapeutic challenge. Substantial evidence demonstrates that an increasing number of long non-coding RNAs are dysregulated in cancer, including the long intergenic non-coding RNA, regulator of reprogramming (linc-ROR), which mostly exerts its role as an onco-lncRNA acting as a competing endogenous RNA that sequesters micro RNAs. Although the properties of linc-ROR in relation to some cancers have been reviewed in the past, active research appends evidence constantly to a better comprehension of the role of linc-ROR in different stages of cancer. Moreover, the molecular details and some recent papers have been omitted or partially reported, thus the importance of this review aimed to contribute to the up-to-date understanding of linc-ROR and its implication in cancer tumorigenesis, progression, metastasis, and chemoresistance. As the involvement of linc-ROR in cancer is elucidated, an improvement in diagnostic and prognostic tools could promote and advance in targeted and specific therapies in precision oncology. [ABSTRACT FROM AUTHOR]

Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a three-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement membrane and embedded in 3D collagen gels to visualize the early events of cancer invasion by confocal microscopy and live-cell imaging. Human breast cancer cells generated large numbers of basement membrane perforations, or holes, of varying sizes that expanded over time during cell invasion. We used a wide variety of small molecule inhibitors to probe the mechanisms of basement membrane perforation and hole expansion. Protease inhibitor treatment (BB94), led to a 63% decrease in perforation size. After myosin II inhibition (blebbistatin), the basement membrane perforation area decreased by only 15%. These treatments produced correspondingly decreased cellular breaching events. Interestingly, inhibition of actin polymerization dramatically decreased basement membrane perforation by 80% and blocked invasion. Our findings suggest that human cancer cells can primarily use proteolysis and actin polymerization to perforate the BM and to expand perforations for basement membrane breaching with a relatively small contribution from myosin II contractility. [ABSTRACT FROM AUTHOR]

Simple Summary: MMP-13 is an enzyme that can digest and disrupt the tissue structures surrounding epithelial cells that line the surface of many internal organs, as well as the tissue structures surrounding endothelial cells that line the surface of blood vessels. The production of MMP-13 is tightly controlled in physiological conditions but is increased in various cancers and plays multiple roles in tumour progression and metastasis. This review summarises the current understanding of the regulation of MMP-13 production and discusses the actions of MMP-13 in cancer progression and metastasis. Matrix metalloproteinase-13 (MMP-13) is a member of the Matrix metalloproteinases (MMPs) family of endopeptidases. MMP-13 is produced in low amounts and is well-regulated during normal physiological conditions. Its expression and secretion are, however, increased in various cancers, where it plays multiple roles in tumour progression and metastasis. As an interstitial collagenase, MMP-13 can proteolytically cleave not only collagens I, II and III, but also a range of extracellular matrix proteins (ECMs). Its action causes ECM remodelling and often leads to the release of various sequestered growth and angiogenetic factors that promote tumour cell growth, invasion and angiogenesis. This review summarizes our current understanding of the regulation of MMP-13 expression and secretion and discusses the actions of MMP-13 in cancer progression and metastasis. [ABSTRACT FROM AUTHOR]

Cancer stem-like cells (CSCs) are a typically small subpopulation of highly tumorigenic cells that can self-renew, differentiate, drive tumor progression, and may mediate drug resistance and metastasis. Metastasis driving CSCs are expected to be highly invasive. To determine the relative invasiveness of CSCs, we isolate distinct subpopulations in the metastatic, MDA-MB-231 breast-cancer cell line, identified by the stem-cell markers aldehyde dehydrogenase (ALDH) and CD44. We determine CSC-subpopulation invasiveness levels using our rapid (2 h) mechanobiology-based assay. Specifically, invasive cells forcefully push and indent the surface of physiological–stiffness synthetic gels to cell-scale depths, where the percentage of indenting cells and their attained depths have previously provided clinically relevant predictions of the metastatic risk in different cancer types. We observe that the small (3.2%) CD44+ALDH+ cell-subpopulation indents more and attains significantly deeper depths (65% indenting to 6 ± 0.3 µm) relative to CD44+ALDH−, CD44−ALDH−, CD44−ALDH+ cells, and the whole-sample control (with 18–44% indenting cells reaching average depths of 4.4–5 µm). The CD44+ALDH+ similarly demonstrates twofold higher migratory capacity in Boyden chambers. The higher invasiveness of CD44+ALDH+ cells reveals their likely role in facilitating disease progression, providing prognostic markers for increased risk of recurrence and metastasis. [ABSTRACT FROM AUTHOR]

The initiation of carcinoma progression is attributed to significant disorders in the synthesis of macromolecules that affect physiological processes in the epithelial cells of oral mucosa. It is known that the integrin family receptors are crucial for regenerative and reparative functions of the normal epithelium. In addition to their well-established physiological role, some types of integrins are the major determinants of malignant transformations. In particular, the results of recent studies in molecular oncology reveal the importance of αv integrins in the pathogenesis of carcinomas, including oral squamous cell carcinoma. This review aims to analyse the significance of αv integrins in the key processes of malignant growth and metastasis of oral squamous cell carcinoma. The prospects of using αv integrins as prognostic molecular markers and targets for developing novel diagnostic and therapeutic methods in the management of oral cancer are discussed.

Background: Transmembrane protein 107 (TMEM107) is a key regulator of the cilium composition and Hedgehog signaling. Lower TMEM107 gene copies are correlated with poor prognosis in non‐small cell lung carcinoma (NSCLC). However, TMEM107 protein expression, localization, and function in NSCLC remain unclear. Methods: We first evaluated TMEM107 expression in 12 newly diagnosed cases of NSCLC and paired adjacent healthy tissues by western blotting. We then used an immunohistochemical method to detect TMEM107 expression in 106 paraffin‐embedded NSCLC and corresponding normal samples and analyzed its relationship with clinicopathological parameters. Moreover, we determined the impact of TMEM107 upregulation and downregulation on invasion, EMT and Hedgehog pathway in NSCLC cells. Results: Our results showed that TMEM107 is localized in the cytoplasm and that its expression was lower in NSCLC. TMEM107 expression was positively correlated with cell differentiation and negatively correlated with lymph node metastasis. In A549 and HCC460 cells, downregulation of TMEM107 facilitated cell invasion and upregulated the expression of the Hedgehog pathway target protein Gli1, invasion‐associated proteins N‐cadherin, vimentin, MMP2, and MMP9, and epithelial‐mesenchymal transition (EMT), and inhibited the expression of E‐cadherin. Treatment with the Hedgehog pathway inhibitor GANT61 attenuated TMEM107‐knockdown–induced EMT and invasiveness. Conclusions: These results indicate that TMEM107 inhibits EMT and invasion by negatively regulating Hedgehog signaling and that it is downregulated in NSCLC. Key points: TMEM107 expression is lower in NSCLC tissues and correlates with poor prognosisTMEM107 inhibits invasion of NSCLC cellsTMEM107 inhibits EMT of NSCLC cellsDownregulation of TMEM107 activates the Hedgehog signaling pathwayDownregulation of TMEM107 promotes EMT and migration in NSCLC by activating the Hedgehog signaling pathway [ABSTRACT FROM AUTHOR]

The study of cancer has allowed researchers to describe some biological characteristics that tumor cells acquire during their development, known as the "hallmarks of cancer" but more research is needed to expand our knowledge about cancer biology and to generate new strategies of treatment. The role that RabGTPases might play in some hallmarks of cancer represents interesting areas of study since these proteins are frequently altered in cancer. However, their participation is not well known. Recently, Rab35was recognized as an oncogenic RabGTPase and and because of its association with different cellular functions, distinctly important in immune cells, a possible role of Rab35 in leukemia can be suggested. Nevertheless, the involvement of Rab35 in cancer remains poorly understood and its possible specific role in leukemia remains unknown. In this review, we analyze general aspects of the participation of RabGTPases in cancer, and especially, the plausible role of Rab35 in leukemia. [ABSTRACT FROM AUTHOR]

Although attempts to develop any viable chemotherapeutic approaches to combat metastatic cancers have largely failed, potential genetic targets to halt metastatic progression continue to be identified. As drugs are developed to address these targets, there is a need for high-throughput systems that accurately reproduce in vivo microenvironments to gauge their efficacy. Accordingly, we have developed a three-dimensional in vitro culture system representative of the environment present upon secondary metastasis to quantitatively measure tumor cell invasion in this setting three-dimensionally. Culturing melanomas of different metastatic capacities within the system showed that each cell type invades the matrix in a manner commensurate to its known metastatic potential in vivo. Moreover, the developed quantitative schemes were put to use to characterize the effect of microenvironmental influences (i.e., matrix components, interstitial cell presence) on planar and vertical melanoma invasion. We propose this novel, quantitative system as a useful tool to assess the effects of pharmacologic and/or microenvironmental influences on tumor cell invasion at a metastatic site.

IL-13Rα2 is a high-affinity binding protein for its ligand IL-13 and a cancer-testis antigen as it is expressed in the testis. IL-13Rα2 is highly expressed in various cancers, including pancreatic cancer, and consists of three domains: extracellular, transmembrane, and cytoplasmic. The extracellular domain binds to the ligand to form a biologically active complex, which initiates signaling through AP-1 and other pathways. IL-13Rα2 is also expressed in diseased cells such as fibroblasts that are involved in various inflammatory diseases, including cancer. We have reported that IL-13Rα2 is a prognostic biomarker for malignant glioma, adrenocortical cancer, and pancreatic cancer. In pancreatic cancer, a small sample of tissue could be examined for the expression of IL-13Rα2 by using the endoscopic ultrasound-fine needle aspiration technique (EUS-FNA). In addition, a peptide-based targeted approach using Pep-1L peptide could be used to study the biodistribution and whole-body cancer imaging for the screening of pancreatic cancer in suspected subjects.

The S100 group of calcium binding proteins is composed of 21 members that exhibit tissue/cell specific expressions. These S100 proteins bind a diverse range of targets and regulate multiple cellular processes, including proliferation, migration and differentiation. S100A10, also known as p11, binds mainly to annexin A2 and mediates the conversion of plasminogen to an active protease, plasmin. Higher S100A10 expression has been reported to link to worse outcome and/or chemoresistance in a number of cancer types in lung, breast, ovary, pancreas, gall bladder and colorectum and leukemia although some discrepancy was reported. In this review, we focused on the roles of the S100A10 in cancer. We summarized its biological functions, role in cancer progression, prognostic value and targeting of S100A10 for cancer therapy. [ABSTRACT FROM AUTHOR]

Background/Aims: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. Methods: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co-immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5-modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. Results: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. Conclusion: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells.

Abstract One of the major causes of death in colorectal cancer (CRC) is invasion and metastasis. Better understanding of the molecular mechanism of CRC invasion and metastasis is essential in developing effective cancer therapies. Cooperative effect of CXCR3 and CXCR4 plays a crucial role in regulating CRC invasion. In present study, we discovered that CRC cells expressing higher levels of CXCR3 and CXCR4 were more invasive. Additionally, CXCR3 formed heteromers with CXCR4 and retained CXCR4 on cell surface. CXCR3 knockdown reduced surface CXCR4 expression and partially inhibited CRC cell invasion. On the contrary, CXCR3 overexpression enhanced surface CXCR4 abundance and promoted CRC cell invasion. Further research indicated that CXCR3-A isoform was responsible for increased CXCR4 surface expression and CRC cell invasion. However, CXCR3-A overexpression without CXCR4 expression did not cause CRC cell invasion, which suggested that CXCR3-A indirectly affect cell invasion through regulating CXCR4. Taken together, CXCR3 enhanced CXCR4 function in CRC cell invasion through forming heteromers with CXCR4 on cell surface and prevent CXCR4 internalization. Therefore, targeting CXCR3 could be a promising strategy for clinical treatment of CRC cell invasion and metastasis. Highlights • Colon cancer cells with both CXCR3 and CXCR4 expression showed significantly stronger invasive phenotype. • In CRC cells, CXCR3 prevented CXCR4 internalization through forming heteromers with CXCR4 on cell surface. • CXCR3-A, instead of CXCR3-B, was mainly responsible for inhibited CXCR4 internalization and enhanced cell invasion. • CRC cells with both CXCR3 and CXCR4 expression showed more metastasis in mice lung tissue after intravenously injections. [ABSTRACT FROM AUTHOR]

In order to move in a three-dimensional extracellular matrix, the nucleus of a cell must squeeze through the narrow spacing among the fibers and, by adhering to them, the cell needs to exert sufficiently strong traction forces. If the nucleus is too stiff, the spacing too narrow, or traction forces too weak, the cell is not able to penetrate the network. In this article, we formulate a mathematical model based on an energetic approach, for cells entering cylindrical channels composed of extracellular matrix fibers. Treating the nucleus as an elastic body covered by an elastic membrane, the energetic balance leads to the definition of a necessary criterion for cells to pass through the regular network of fibers, depending on the traction forces exerted by the cells (or possibly passive stresses), the stretchability of the nuclear membrane, the stiffness of the nucleus, and the ratio of the pore size within the extracellular matrix with respect to the nucleus diameter. The results obtained highlight the importance of the interplay between mechanical properties of the cell and microscopic geometric characteristics of the extracellular matrix and give an estimate for a critical value of the pore size that represents the physical limit of migration and can be used in tumor growth models to predict their invasive potential in thick regions of ECM. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) constitutes the most aggressive tumors of the oral cavity and is one of the leading causes of cancer mortality worldwide. Although recent clinical treatment strategies have improved the survival rate, the outcome of OSCC patients still remains dismal because of the lack of efficient diagnostic and treatment tools. As one of the main actors of OSCC scenario, microRNAs (miRNAs) are involved in triggering, progression and metastasis through the regulation of various cancer-related signaling pathways. Identification followed by precise study of the biology and mechanism of action of miRNAs will greatly help to provide valuable insights regarding OSCC development and can be considered as an anti-OSCC target. In the current review, we have provided a focused summary of the latest published papers on the role of miRNAs in apoptosis, cell cycle, proliferation, EMT and metastasis of OSCC as well as the role of long noncoding RNAs in the modulation of miRNAs in OSCC. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the leading causes of death in both males and females, and it is the first causes of cancer-related deaths. Chemotherapy, surgery and radiotherapy are conventional treatment of lung cancer and recently, immunotherapy has been also appeared as another therapeutic strategy for lung tumor. However, since previous treatments have not been successful in cancer therapy and improving prognosis and survival rate of lung tumor patients, new studies have focused on gene therapy and targeting underlying molecular pathways involved in lung cancer progression. Nanoparticles have been emerged in treatment of lung cancer that can mediate targeted delivery of drugs and genes. Nanoparticles protect drugs and genes against unexpected interactions in blood circulation and improve their circulation time. Nanoparticles can induce phototherapy in lung cancer ablation and mediating cell death. Nanoparticles can induce photothermal and photodynamic therapy in lung cancer. The nanostructures can impair metastasis of lung cancer and suppress EMT in improving drug sensitivity. Metastasis is one of the drawbacks observed in lung cancer that promotes migration of tumor cells and allows them to establish new colony in secondary site. EMT can occur in lung cancer and promotes tumor invasion. EMT is not certain to lung cancer and it can be observed in other human cancers, but since lung cancer has highest incidence rate, understanding EMT function in lung cancer is beneficial in improving prognosis of patients. EMT induction in lung cancer promotes tumor invasion and it can also lead to drug resistance and radio-resistance. Moreover, non-coding RNAs and pharmacological compounds can regulate EMT in lung cancer and EMT-TFs such as Twist and Slug are important modulators of lung cancer invasion that are discussed in current review. [Display omitted] • The most common malignancy in both sexes in lung cancer with a multifactorial etiology. • Nanostructures can deliver drugs and genes and promote their internalization in cancer cells. • Nanostructures stimulate photothermal and photodynamic therapy in eradicating lung tumor cells. • Nanostructures suppress metastasis of lung cancer and inhibit EMT in drug sensitivity. • EMT promotes invasion and metastasis of lung cancer cells and can mediate chemoresistance. [ABSTRACT FROM AUTHOR]

Cancer invasion and metastasis accounts for the majority of cancer related mortality. A better understanding of the players that drive the aberrant invasion and migration of tumors cells will provide critical targets to inhibit metastasis. Postnatal pubertal mammary gland morphogenesis is characterized by highly proliferative, invasive, and migratory normal epithelial cells. Identifying the molecular regulators of pubertal gland development is a promising strategy since tumorigenesis and metastasis is postulated to be a consequence of aberrant reactivation of developmental stages. In this review, we summarize the pubertal morphogenesis regulators that are involved in cancer metastasis and revisit pubertal mammary gland transcriptome profiling to uncover both known and unknown metastasis genes. Our updated list of pubertal morphogenesis regulators shows that most are implicated in invasion and metastasis. This review highlights molecular linkages between development and metastasis and provides a guide for exploring novel metastatic drivers. • Additional molecular targets are needed to combat tumor invasion and metastasis. • Developmental biology can provide novel insights in cancer invasion and metastasis. • Developmental motility genes are aberrantly hijacked by metastatic tumors. • List of potential therapeutic targets for cancer invasion and metastasis. • Transcriptomic gene signature for the Terminal End Bud of pubertal mammary gland. [ABSTRACT FROM AUTHOR]

The predominant kind of liver cancer is hepatocellular carcinoma (HCC) that its treatment have been troublesome difficulties for physicians due to aggressive behavior of tumor cells in proliferation and metastasis. Moreover, stemness of HCC cells can result in tumor recurrence and angiogenesis occurs. Another problem is development of resistance to chemotherapy and radiotherapy in HCC cells. Genomic mutations participate in malignant behavior of HCC and nuclear factor-kappaB (NF-κB) has been one of the oncogenic factors in different human cancers that after nuclear translocation, it binds to promoter of genes in regulating their expression. Overexpression of NF-κB has been well-documented in increasing proliferation and invasion of tumor cells and notably, when its expression enhances, it induces chemoresistance and radio-resistance. Highlighting function of NF-κB in HCC can shed some light on the pathways regulating progression of tumor cells. The first aspect is proliferation acceleration and apoptosis inhibition in HCC cells mediated by enhancement in expression level of NF-κB. Moreover, NF-κB is able to enhance invasion of HCC cells via upregulation of MMPs and EMT, and it triggers angiogenesis as another step for increasing spread of tumor cells in tissues and organs. When NF-κB expression enhances, it stimulates chemoresistance and radio-resistance in HCC cells and by increasing stemness and population of cancer-stem cells, it can provide the way for recurrence of tumor. Overexpression of NF-κB mediates therapy resistance in HCC cells and it can be regulated by non-coding RNAs in HCC. Moreover, inhibition of NF-κB by anti-cancer and epigenetic drugs suppresses HCC tumorigenesis. More importantly, nanoparticles are considered for suppressing NF-κB axis in cancer and their prospectives and results can also be utilized for treatment of HCC. Nanomaterials are promising factors in treatment of HCC and by delivery of genes and drugs, they suppress HCC progression. Furthermore, nanomaterials provide phototherapy in HCC ablation. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary Cancer metastases arise from a multi-step process that requires metastasizing tumor cells to adapt to signaling input from varying tissue environments [ 1 ]. As an early metastatic event, cancer cell dissemination occurs through different migration programs, including multicellular, collective, and single-cell mesenchymal or amoeboid migration [ 2–4 ]. Migration modes can interconvert based on changes in cell adhesion, cytoskeletal mechanotransduction [ 5 ], and/or proteolysis [ 6 ], most likely under the control of transcriptional programs such as the epithelial-to-mesenchymal transition (EMT) [ 7, 8 ]. However, how plasticity of tumor cell migration and EMT is spatiotemporally controlled and connected upon challenge by the tumor microenvironment remains unclear. Using 3D cultures of collectively invading breast and head and neck cancer spheroids, here we identify hypoxia, a hallmark of solid tumors [ 9 ], as an inducer of the collective-to-amoeboid transition (CAT), promoting the dissemination of amoeboid-moving single cells from collective invasion strands. Hypoxia-induced amoeboid detachment was driven by hypoxia-inducible factor 1 (HIF-1), followed the downregulation of E-cadherin, and produced heterogeneous cell subsets whose phenotype and migration were dependent (∼30%) or independent (∼70%) of Twist-mediated EMT. EMT-like and EMT-independent amoeboid cell subsets showed stable amoeboid movement over hours as well as leukocyte-like traits, including rounded morphology, matrix metalloproteinase (MMP)-independent migration, and nuclear deformation. Cancer cells undergoing pharmacological stabilization of HIFs retained their constitutive ability for early metastatic seeding in an experimental model of lung metastasis, indicating that hypoxia-induced CAT enhances cell release rather than early organ colonization. Induced by metabolic challenge, amoeboid movement may thus constitute a common endpoint of both EMT-dependent and EMT-independent cancer dissemination programs. [ABSTRACT FROM AUTHOR]

Cell membranes are the reason of the cell energy transfer. In cells energy transfer, thermo-electro-chemical processes and transports phenomena occur through their membranes. Cells can actively modify their behaviours in relation to any change of their environment. They waste heat into their environment. The analysis of irreversibility related to this wasted heat, to the ions transport and the related cell-environment pH changes represents a new useful approach to the study of the cells behaviour. This analysis allows also the explanation of the effects of electromagnetic fields on the cell behaviour, and to suggest how low intensity electromagnetic fields could represent a useful support to the present anticancer therapies. [ABSTRACT FROM AUTHOR]

The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach. [ABSTRACT FROM AUTHOR]

Mixed-lineage kinase 3 (MLK3) was first cloned in 1994; however, only in the past decade has MLK3 become recognized as a player in oncogenic signaling. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates signals from several cell surface receptors including receptor tyrosine kinases (RTKs), chemokine receptors, and cytokine receptors. Once activated, MLK3 transduces signals to multiple downstream pathways, primarily to c-Jun terminal kinase (JNK) MAPK, as well as to extracellular-signal-regulated kinase (ERK) MAPK, P38 MAPK, and NF-κB, resulting in both transcriptional and post-translational regulation of multiple effector proteins. In several types of cancer, MLK3 signaling is implicated in promoting cell proliferation, as well as driving cell migration, invasion and metastasis. [ABSTRACT FROM AUTHOR]

Mechanical features of cancer cells emerge as a distinct trait during development and progression of solid tumors. Herein, we discuss recent key findings regarding the impact of various types of mechanical stresses on cancer cell properties. Data suggest that different mechanical forces, alterations of matrix rigidity and tumor microenvironment facilitate cancer hallmarks, especially invasion and metastasis. Moreover, a subset of mechanosensory proteins are responsible for mediating mechanically induced oncogenic signaling and response to chemotherapy. Delineating cancer dynamics and decoding of respective signal transduction mechanisms will provide new therapeutic strategies against solid tumors in the future. • Cancer biomechanics impacts on different aspects of solid tumors. • ECM rigidity affects development and progression of solid tumors. • Membrane structures convey signals to establish metastatic phenotypic changes. • Mechanosensory proteins regulate cell invasion and metastasis of solid tumors. • Aberrant mechanical inputs contribute to molecular mechanisms of drug resistance. [ABSTRACT FROM AUTHOR]

Background/Aims: The aggressive manner of ovarian cancer (OVC) cells accounts for the majority of its lethality. Recently, we have shown that placental growth factor (PLGF) promotes metastases of OVC cells through miR-543-regulated MMP7. In the current study, we analyzed the effects of PLGF on another cell invasion associated protein, ZEB2, in OVC cells. Methods: The PLGF and ZEB2 levels in OVC tissues were compared to the paired adjacent non-tumor ovary tissue. We modified ZEB2 levels in OVC cells, and examined its effects on PLGF mRNA and protein levels by RT-qPCR and by Western blot, respectively. We also modified PLGF levels in OVC cells, and examined its effects on ZEB2 mRNA and protein levels by RT-qPCR and by Western blot, respectively. Then, we examined the cell invasiveness in PLGF-modified OVC cells in a transwell cell invasion assay. Finally, we used specific signal pathway inhibitors to treat PLGF-modified OVC cells and examined the effects on ZEB2 activation. Results: PLGF and ZEB2 levels were both significantly increased in OVC tissues, compared to the paired adjacent non-tumor ovary tissue. The PLGF and ZEB2 levels were strongly correlated. ZEB2 modification did not alter PLGF levels. Overexpression of PLGF in OVC cells significantly increased ZEB2 levels and cell invasiveness, while PLGF depletion in OVC cells significantly decreased ZEB2 levels and cell invasiveness. Application of a specific MAPK-p38 inhibitor, but not application of specific inhibitors for MAPK-p42/p44, PI3k/Akt, or JNK signaling pathways, to PLGF-overexpressing OVC cells substantially abolished the PLGF-induced ZEB2 activation. Conclusion: PLGF enhances OVC cell invasion through MAPK-p38-dependent activation of ZEB2. © 2016 The Author(s) Published by S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs-mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well. [ABSTRACT FROM AUTHOR]

Invasion and metastasis are malignant phenotypes in cancer that lead to patient death. Cell motility is involved in these processes. In 1998, we identified overexpression of the actin-bundling protein actinin-4 in several types of cancer. Protein expression of actinin-4 is closely associated with the invasive phenotypes of cancers. Actinin-4 is predominantly expressed in the cellular protrusions that stimulate the invasive phenotype in cancer cells and is essential for formation of cellular protrusions such as filopodia and lamellipodia. ACTN4 (gene name encoding actinin-4 protein) is located on human chromosome 19q. ACTN4 amplification is frequently observed in patients with carcinomas of the pancreas, ovary, lung, and salivary gland, and patients with ACTN4 amplifications have worse outcomes than patients without amplification. In addition, nuclear distribution of actinin-4 is frequently observed in small cell lung, breast, and ovarian cancer. Actinin-4, when expressed in cancer cell nuclei, functions as a transcriptional co-activator. In this review, we summarize recent developments regarding the biological roles of actinin-4 in cancer invasion. [ABSTRACT FROM AUTHOR]

Background/Aims: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. Methods: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co-immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5-modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. Results: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. Conclusion: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study was performed to elucidate the effect of a lipid-soluble ginseng extract (LSGE) on cancer invasion and metastasis. The LSGE, even at noncytotoxic concentrations, potently inhibited invasion and migration of B16F10 mouse melanoma cells in a dose-dependent manner. In the presence of 3 μg/mL of LSGE, the invasion and migration of B16F10 cells were significantly inhibited by 98.1% and 71.4%, respectively. Furthermore, the LSGE decreased mRNA and protein levels of matrix metalloproteinase (MMP)-2 in B16F10 cells, leading to a decrease in MMP-2 activity. After B16F10 cells were intravenously injected in the tail vein of C57BL/6 mice, 1000 mg/kg/day of LSGE was orally administered for 13 days, after which lung metastasis of cancer cells was inhibited by 59.3%. These findings indicate that LSGE inhibits cancer cell invasion and migration in vitro and lung metastasis of melanoma cells in vivo by inhibiting MMP-2 expression. [ABSTRACT FROM AUTHOR]

Galectins are a family of proteins that contain a canonical carbohydrate-recognition domain (CRD) with affinity for beta-galactosides. Within this family, an unique member, the chimeric, galectin-3, may be found in the cytoplasm and nucleus, and on the cell surface, besides being released into the extracellular space. Galectin-3 interactions with certain glycans and extracellular matrix (ECM) proteins have been described to promote and/or antagonize tumor cell apoptosis, to induce endothelial cell proliferation and angiogenesis, and to promote tumor cell adhesion and invasion, thus both potentially facilitating and hindering metastasis. Moreover, although galectin-3 is expressed in several types of malignancies and its expression has been correlated with transformation and metastasis-related events, its downregulation has also been associated with malignancy and tumor progression. These apparently conflicting data demonstrate that the role of galectin-3 in metastasis remains to be fully understood. Of course in nature, different cancer progression phenomena are simultaneously occurring in the many instances, where the patient has primary tumor and blood-borne and distant metastatic cells. This makes it all the more interesting to overview the role of galectins in cancer metastasis, especially galectin-3, since these and their related molecules are more than probable disease marker candidates and/or therapeutic targets. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC. [ABSTRACT FROM AUTHOR]

Oncogenic PI3K/mTOR activation is frequently observed in human cancers and activates cell motility via p27 phosphorylations at T157 and T198. Here we explored the potential for a novel PI3K/mTOR inhibitor to inhibit tumor invasion and metastasis. An MDA-MB-231 breast cancer line variant, MDA-MB-231-1833, with high metastatic bone tropism, was treated with a novel catalytic PI3K/mTOR inhibitor, PF-04691502, at nM doses that did not impair proliferation. Effects on tumor cell motility, invasion, p27 phosphorylation, localization, and bone metastatic outgrowth were assayed. MDA-MB-231-1833 showed increased PI3K/mTOR activation, high levels of cytoplasmic p27pT157pT198 and increased cell motility and invasion in vitro versus parental. PF-04691502 treatment, at a dose that did not affect proliferation, reduced total and cytoplasmic p27, decreased p27pT157pT198 and restored cell motility and invasion to levels seen in MDA-MB-231. p27 knockdown in MDA-MB-231-1833 phenocopied PI3K/mTOR inhibition, whilst overexpression of the phosphomimetic mutant p27T157DT198D caused resistance to the anti-invasive effects of PF-04691502. Pre-treatment of MDA-MB-231-1833 with PF-04691502 significantly impaired metastatic tumor formation in vivo, despite lack of antiproliferative effects in culture and little effect on primary orthotopic tumor growth. A further link between cytoplasmic p27 and metastasis was provided by a study of primary human breast cancers which showed cytoplasmic p27 is associated with increased lymph nodal metastasis and reduced survival. Novel PI3K/mTOR inhibitors may oppose tumor metastasis independent of their growth inhibitory effects, providing a rationale for clinical investigation of PI3K/mTOR inhibitors in settings to prevent micrometastasis. In primary human breast cancers, cytoplasmic p27 is associated with worse outcomes and increased nodal metastasis, and may prove useful as a marker of both PI3K/mTOR activation and PI3K/mTOR inhibitor efficacy. [ABSTRACT FROM AUTHOR]

Summary: The incidence of distant metastasis in head and neck squamous cell carcinoma (HNSCC) is relatively low but remains a major determinant of prognosis and therefore an important factor in clinical decision making. The most frequently involved sites for distant metastasis are the lung (approximately 70% of cases), followed by bone and liver. There are often conflicting reports on which parameters are risk factors for distant metastasis, but the most important predictive factors appear to be the site of the primary tumor (hypopharynx in particular), advanced T- and N-classification, histological grade and the ability to achieve locoregional disease control. Metastasis results from a selection of tumor cells that have acquired the properties to withstand multiple and often unfavorable circumstances and settle in distant organs. Most of these processes involve interaction between tumor cells, their microenvironment and host factors. Increasing knowledge of the biology of distant metastasis may result in the development of diagnostic and therapeutic strategies targeted to this usually terminal stage for patients with HNSCC. [ABSTRACT FROM AUTHOR]

Background: Proteolytic degradation of the extracellular matrix (ECM) is a key event in tumour metastasis and invasion. Matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade most of the components of the ECM. Several broadspectrum MMP inhibitors (MMPIs) have been developed, but have had little success due to side effects. Thus, it is important to develop mathematical methods to provide new drug treatment strategies. Matrix metalloproteinase 2 (MMP2) activation occurs via a mechanism involving complex formation that consists of membrane type 1 MMP (MT1-MMP), tissue inhibitor of matrix metalloproteinase 2 (TIMP2) and MMP2. Here, we focus on developing a method for analysing the complex formation process. Results: We used control analysis to investigate inhibitor responses in complex formation processes. The essence of the analysis is to define the response coefficient which measures the inhibitory efficiency, a small fractional change of concentration of a targeting molecule in response to a small fractional change of concentration of an inhibitor. First, by using the response coefficient, we investigated models for general classes of complex formation processes: chain reaction systems composed of ordered steps, and chain reaction systems and site-binding reaction systems composed of unordered multi-branched steps. By analysing the ordered step models, we showed that parameter-independent inequalities between the response coefficients held. For the unordered multi-branched step models, we showed that independence of the response coefficients with respect to equilibrium constants held. As an application of our analysis, we discuss a mathematical model for the MMP2 activation process. By putting the experimentally derived parameter values into the model, we were able to conclude that the TIMP2 and MMP2 interaction is the most efficient interaction to consider in selecting inhibitors. Conclusions: Our result identifies a new drug target in the process of the MMP2 activation. Thus, our analysis will provide new insight into the design of more efficient drug strategies for cancer treatment. [ABSTRACT FROM AUTHOR]

Myoferlin (MYOF) is a member of the evolutionarily conserved ferlin family of proteins, noted for their role in a variety of membrane processes, including endocytosis, repair, and vesicular transport. Notably, ferlins are implicated in Caenorhabditis elegans sperm motility (Fer-1), mammalian skeletal muscle development and repair (MYOF and dysferlin), and presynaptic transmission in the auditory system (otoferlin). In this paper, we demonstrate that MYOF plays a previously unrecognized role in cancer cell invasion, using a combination of mathematical modeling and in vitro experiments. Using a real-time impedance-based invasion assay (xCELLigence), we have shown that lentiviral-based knockdown of MYOF significantly reduced invasion of MDA-MB-231 breast cancer cells in Matrigel bioassays. Based on these experimental data, we developed a partial differential equation model of MYOF effects on cancer cell invasion, which we used to generate mechanistic hypotheses. The mathematical model predictions revealed that matrix metalloproteinases (MMPs) may play a key role in modulating this invasive property, which was supported by experimental data using quantitative RT-PCR screens. These results suggest that MYOF may be a promising target for biomarkers or drug target for metastatic cancer diagnosis and therapy, perhaps mediated through MMPs. [ABSTRACT FROM AUTHOR]

The formation of aqueous intercellular channels mediating gap junctional intercellular coupling (GJIC) is a canonical function of connexins (Cx). In contrast, mechanisms of GJIC-independent involvement of connexins in cancer formation and metastasis remain a matter of debate. Because of the role of Cx43 in the determination of carcinoma cell invasive potential, we addressed the problem of the possible Cx43 involvement in early prostate cancer invasion. For this purpose, we analysed Cx43-positive DU-145 cell subsets established from the progenies of the cells most readily transmigrating microporous membranes. These progenies displayed motile activity similar to the control DU-145 cells but were characterized by elevated Cx43 expression levels and GJIC intensity. Thus, apparent links exist between Cx43 expression and transmigration potential of DU-145 cells. Moreover, Cx43 expression profiles in the analysed DU-145 subsets were not affected by intercellular contacts and chemical inhibition of GJIC during the transmigration. Our observations indicate that neither cell motility nor GJIC determines the transmigration efficiency of DU-145 cells. However, we postulate that selective transmigration of prostate cancer cells expressing elevated levels of Cx43 expression may be crucial for the 'leading front' formation during cancer invasion. [ABSTRACT FROM AUTHOR]

Abstract: During cancer invasion, the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of a cancer cell is considered a trigger for invasion. Here, we present a stable structure of the solvated complex formed between uPA and uPAR (uPA–uPAR) and investigate the specific interactions between uPA and uPAR by ab initio fragment molecular orbital (FMO) calculations. The result indicates that the electrostatic interactions between the charged amino acid residues existing in both uPA and uPAR make a large contribution to the binding between uPA and uPAR. In particular, Lys23, Lys46, Lys98 and Lys61 of uPA are found to have strong attractive interactions with uPAR. To elucidate the effect of these residues on the interactions between uPA and uPAR, we substituted each of them with the uncharged amino acid Leu and investigated the interactions between the mutated uPA and wild-type uPAR. The interaction energies indicate that Lys46 and Lys98, which bind uPA to the rim of the central ligand-binding cavity of uPAR, make greater contributions to the binding between uPA and uPAR than Lys23, which is positioned at the bottom of the ligand-binding cavity of uPAR. The effect of hydrating water molecules located between uPA and uPAR is also investigated to be significant for the specific interactions between uPA and uPAR. These results are expected to be informative for developing new peptide antagonists that block the binding of uPA to uPAR. [Copyright &y& Elsevier]

Matrix metallaprotinase-9 (MMP-9) is zinc-containing proteinase whose expression and trafficking are frequently altered in cancer. MMP-9 in the plasma membrane and the secreted forms are thought to contribute to the invasive and metastatic properties of malignant tumors. We have manipulated the expression of MMP-9 in prostate tumor cell line LNCaP and measured their capacity to invade through a basement membrane matrix. Stable expression of human MMP-9 in a poorly metastatic LNCaP prostate cancer cell line produced a 2-3-fold increase in MMP-9 activity and a comparable increase in invasiveness. Transient transfection of LNCaP stable clone expressing MMP-9 with MMP-9 antisense oligonucleotide (ASODN) produced 55--90%% less MMP-9 than control cells and were proportionately less invasive. In contrast, manipulating MMP-9 levels had no effect on cell migration across an uncoated membrane. A standard MMP-9 inhibitor at a concentration ranging from 1--10 nM, caused a nearly quantitative inhibition of extracellular MMP-9 activity and had significant effect on basement membrane invasion. Collectively, these results confirm the role of MMP-9 in tissue remodeling associated with prostate tumor invasion. [ABSTRACT FROM AUTHOR]