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

Long-range mechanical force in colony branching and tumor invasion

The most concerned factors for cancer prognosis are tumor invasion and metastasis. The patterns of tumor invasion can be characterized as random infiltration to surrounding extracellular matrix (ECM) or formation of long-range path for collective migration. Recent studies indicate that mechanical force plays an important role in tumor infiltration and collective migration. However, how tumor colonies develop mechanical interactions with each other to initiate various invasion patterns is unclear. Using a micro-patterning technique, we partition cells into clusters to mimic tumor colonies and quantitatively induce colony-ECM interactions. We find that pre-malignant epithelial cells, in response to concentrations of type I collagen in ECM ([COL]), develop various branching patterns resembling those observed in tumor invasion. In contrast with conventional thought, these patterns require long-range (~ 600 μm) transmission of traction force, but not biochemical factors. At low [COL], cell colonies synergistically develop pairwise and directed branching mimicking the formation of long-range path. By contrast, at high [COL] or high colony density, cell colonies develop random branching and scattering patterns independent of each other. Our results suggest that tumor colonies might select different invasive patterns depending on their interactions with each other and with the ECM

Exosomes promote pre-metastatic niche formation in ovarian cancer.

Ovarian cancer is one of the most common gynecological malignancies. Upon initial diagnosis, the majority of patients present with widespread metastatic growth within the peritoneal cavity. This metastatic growth occurs in stages, with the formation of a pre-metastatic niche occurring prior to macroscopic tumor cell invasion. Exosomes released by the primary ovarian tumor are small extracellular vesicles which prepare the distant tumor microenvironment for accelerated metastatic invasion. They regulate intercellular communication between tumor cells and normal stroma, cancer-associated fibroblasts, and local immune cells within the tumor microenvironment. In this review, we highlight the emerging roles of ovarian cancer exosomes as coordinators of pre-metastatic niche formation, biomarkers amenable to liquid biopsy, and targets of chemotherapy

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

The tumor-promoting functions of Ataxia-telangiectasia mutated (ATM) in cancer cells

textAtaxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression by protecting cells from DNA double-strand breaks (DSBs). However, how ATM functions outside of DSB signaling is less clearly understood. Here, we report a new cancer-promoting role for ATM in stimulating cell migration and invasion independently of DSB signaling or induction. We used two highly metastatic human breast cancer cell lines to corroborate that ATM is required for cell migration and invasion. Microarray analysis of cells depleted for ATM identified interleukin-8 (IL-8) as a target since the exogenous addition of IL-8 rescued migration and invasion defects in ATM-deficient cells. Finally, ATM depletion in human cancer cells reduced lung metastasis in a mouse xenograft model. These findings shed light on tumor-promoting functions of ATM. Therefore, in addition to its canonical roles in tumor suppression, ATM promotes tumor progression as well.Cellular and Molecular Biolog

Endoscopic Mucosal Resection of Primary Anorectal Malignant Melanoma:A Case Report

Anorectal melanoma is a rare malignant tumor with a poor prognosis. However, several studies have reported cases of long-term survival. In this report, we present a patient with anorectal melanoma who has survived for 9 years after endoscopic mucosal resection. An 85-year-old man was referred to our hospital for further examination and treatment of an anal tumor 2cm in size. Endoscopic ultrasonography revealed that the depth of tumor invasion was confined to the submucosal layer. Endoscopic mucosal resection was performed, and the tumor was diagnosed as a malignant melanoma. The patient was followed without any additional treatment, which was per his wishes. Although melanoma recurred 4 times thereafter, endoscopic mucosal resection was performed for each recurrent lesion. Thus, he has been alive for 9 years since the first endoscopic mucosal resection without distant metastases. If the depth of tumor invasion is shallow, endoscopic mucosal resection is a useful option among other therapeutic modalities.</p

Down-regulation of myopodin expression reduces invasion and motility of PC-3 prostate cancer cells

Enhanced motility of cancer cells by remodelling of the actin cytoskeleton is crucial in the process of cancer cell invasion and metastasis. Although several studies propose a tumor suppressor role for the actin bundling protein myopodin, it was also shown previously that overexpression of mouse myopodin promotes invasion in vitro. In the present study, the role of myopodin in human cancer cell motility and invasion was explored using RNA interference with siRNA duplexes designed to down-regulate all human myopodin isoforms currently identified. We show that down-regulation of myopodin expression in human cancer cells significantly reduces the invasive properties of these cells both in collagen type I and in Matrigel (R). Furthermore, the motile characteristics of cancer cells are also curbed by reduced myopodin expression whereas cell-cell contacts are reinforced. These results point to a role for myopodin as tumor activator. While these findings are at variance with the suggested tumor suppressor role for myopodin, we hypothesize that the subcellular localization of the protein is involved in its suppressor or activator function in tumorigenesis

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

Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome