Probabilistic approach to a proliferation and migration dichotomy in the tumor cell invasion

The proliferation and migration dichotomy of the tumor cell invasion is examined within a two-component continuous time random walk (CTRW) model. The balance equations for the cancer cells of two phenotypes with random switching between cell proliferation and migration are derived. The transport of tumor cells is formulated in terms of the CTRW with an arbitrary waiting time distribution law, while proliferation is modelled by a logistic growth. The overall rate of tumor cell invasion for normal diffusion and subdiffusion is determined.Comment: Accepted for publication as a Regular Article in Physical Review

Migration and proliferation dichotomy in tumor cell invasion

We propose a two-component reaction-transport model for the migration-proliferation dichotomy in the spreading of tumor cells. By using a continuous time random walk (CTRW) we formulate a system of the balance equations for the cancer cells of two phenotypes with random switching between cell proliferation and migration. The transport process is formulated in terms of the CTRW with an arbitrary waiting time distribution law. Proliferation is modeled by a standard logistic growth. We apply hyperbolic scaling and Hamilton-Jacobi formalism to determine the overall rate of tumor cell invasion. In particular, we take into account both normal diffusion and anomalous transport (subdiffusion) in order to show that the standard diffusion approximation for migration leads to overestimation of the overall cancer spreading rate.Comment: 9 page

Role of the Endothelium during Tumor Cell Metastasis: Is the Endothelium a Barrier or a Promoter for Cell Invasion and Metastasis?

The malignancy of cancer disease depends on the ability of the primary tumor to metastasize to distant organs. The process of the metastasis formation has largely been analyzed, but still main pathways regarding the extravasation step at the end of the metastasis formation process are controversially discussed. An agreement has been reached about the importance of the endothelium to promote metastasis formation either by enhancing the growth of the primary tumor or by homing (targeting) the tumor cells to blood or lymph vessels. The mechanical properties of the invading tumor cells become the focus of several studies, but the endothelial cell mechanical properties are still elusive. This paper describes the different roles of the endothelium in the process of metastasis formation and focuses on a novel role of the endothelium in promoting tumor cell invasion. It discusses how novel biophysical tools and in vivo animal models help to determine the role of the endothelium in the process of tumor cell invasion. Evidence is provided that cell mechanical properties, for example, contractile force generation of tumor cells, are involved in the process of tumor cell invasion

Modulation of CXCR4, CXCL12, and Tumor Cell Invasion Potential In Vitro by Phytochemicals.

CXCR4 is a chemokine receptor frequently overexpressed on primary tumor cells. Organs to which these cancers metastasize secrete CXCL12, the unique ligand for CXCR4, which stimulates invasion and metastasis to these sites. Similar to our previous work with the chemoprotective phytochemical, 3,3'-diindolylmethane (DIM), we show here that genistein also downregulates CXCR4 and CXCL12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells. Moreover, genistein and DIM elicit a significantly greater cumulative effect in lowering CXCR4 and CXCL12 levels than either compound alone. Our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination, these compounds may prove even more efficacious

Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements.

Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. SNPH ubiquitination did not result in protein degradation, but instead anchored SNPH on tubulin to inhibit mitochondrial motility and cycles of organelle fusion and fission, that is dynamics. Expression of ubiquitination-defective SNPH mutant Lys111!Arg or Lys153!Arg increased the speed and distance traveled by mitochondria, repositioned mitochondria to the cortical cytoskeleton, and supported heightened tumor chemotaxis, invasion, and metastasis in vivo. Interference with SNPH ubiquitination activated mitochondrial dynamics, resulting in increased recruitment of the fission regulator dynamin-related protein-1 (Drp1) to mitochondria and Drp1-dependent tumor cell motility. These data uncover nondegradative ubiquitination of SNPH as a key regulator of mitochondrial trafficking and tumor cell motility and invasion. In this way, SNPH may function as a unique, ubiquitination-regulated suppressor of metastasis

CD155/PVR plays a key role in cell motility during tumor cell invasion and migration

BACKGROUND: Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. METHODS: We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. RESULTS: Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and αv-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. CONCLUSION: These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis

Hyaluronan-CD44 interaction promotes microRNA signaling and RhoGTPase activation leading to tumor progression.

A hallmark of all solid tumor malignancies is the ability to invade the surrounding tissue and/or metastasize to distant sites. Tumors cells have altered signaling pathways which that to cytoskeleton activation and migration. Myriad studies have attempted to identify specific adhesion molecule(s) expressed in solid tumor cells that correlate with tumor cell migrative and invasive behaviors. Among such candidate molecules is hyaluronan (HA), the major glycosaminoglycan component of extracellular matrix (ECM). HA serves not only as a primary constituent of connective tissue extracellular matrices but also functions as a bio-regulatory molecule. Pertinently, HA is enriched in many types of tumors. HA is capable of binding to CD44 which is a ubiquitous, abundant and functionally important receptor expressed on the surface of many normal cells and tumor cells. Several lines of evidence indicate that CD44 selects its unique downstream effectors and coordinates downstream, intracellular signaling pathways that influence multiple cellular functions. Certain microRNAs [(miRNAs), small RNA molecules with ~20-25 nucleotides] have been shown to play roles in regulating tumor cell migration, invasion, survival and chemotherapy resistance. In this article, a special focus is placed on the role of HA-mediated CD44 interaction with unique signaling molecules in activating intracellular miRNA-signaling and RhoGTPase functions leading to the concomitant onset of tumor cell activities (e.g., tumor cell migration, invasion, survival and chemoresistance) and tumor progression. This new knowledge could serve as groundwork for the future development of new drug targets to inhibit HA/CD44-mediated oncogenic signaling and cancer progression

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin’s influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites