Metastatic Dissemination Of Cancer Cells Research Articles

Escaping from, moving towards, following a path, squeezing through: lots of opportunities for moving cells.

Eukaryotic cells move within the surrounding environment essentially for two reasons: the necessity to reach a predetermined site or the hostility of the primitive site. Moving in the direction of an attractive site or factor is typical for embryonic movements and metastatic dissemination of cancer cells and motility strategies are very similar for both categories. Activation of an epigenetic process called epithelial mesenchymal transition (EMT) is indeed characteristic of embryonic development, of fibrotic or regeneration processes, and of the spreading of cancer cells from their primitive origin

Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors

A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of 27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility of generating fragment libraries enriched in heparanase inhibitors.

Heparanase Augments Epidermal Growth Factor Receptor Phosphorylation: Correlation with Head and Neck Tumor Progression

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains, a class of glycosaminoglycans abundantly present in the extracellular matrix and on the cell surface. Heparanase activity is strongly implicated in tumor metastasis attributed to remodeling of the subepithelial and subendothelial basement membranes, resulting in dissemination of metastatic cancer cells. Moreover, heparanase up-regulation was noted in an increasing number of primary human tumors, correlating with tumors larger in size, increased microvessel density, and reduced postoperative survival rate, implying that heparanase function is not limited to tumor metastasis. This notion is supported by recent findings revealing induction of signaling molecules (i.e., Akt, p38) and gene transcription [i.e., tissue factor, vascular endothelial growth factor (VEGF)] by enzymatically-inactive heparanase. Here, we provide evidence that active and inactive heparanase proteins enhance epidermal growth factor receptor (EGFR) phosphorylation. Enhanced EGFR phosphorylation was associated with increased cell migration, cell proliferation, and colony formation, which were attenuated by Src inhibitors. Similarly, heparanase gene silencing by means of siRNA was associated with reduced Src and EGFR phosphorylation levels and decreased cell proliferation. Moreover, heparanase expression correlated with increased phospho-EGFR levels and progression of head and neck carcinoma, providing a strong clinical support for EGFR modulation by heparanase. Thus, heparanase seems to modulate two critical systems involved in tumor progression, namely VEGF expression and EGFR activation. Neutralizing heparanase enzymatic and nonenzymatic functions is therefore expected to profoundly affect tumor growth, angiogenesis, and metastasis.

Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence

Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.

Extracellular matrix protein βig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation

Metastasis, the major cause of cancer death, is a multistep process that requires interactions between cancer cells and stromal cells and between cancer cells and extracellular matrix. Molecular alterations of the extracellular matrix in the tumor microenvironment have a considerable impact on the metastatic process during tumorigenesis. Here we report that elevated expression of betaig-h3/TGFBI (transforming growth factor, beta-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the betaig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of betaig-h3 expression dramatically reduced metastasis. Mechanistically, betaig-h3 appears to promote extravasation, a critical step in the metastatic dissemination of cancer cells, by inducing the dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin alphavbeta5-Src signaling pathway. Thus, cancers associated with overexpression of betaig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.