Functional blocking of specific integrins inhibit colonic cancer migration

Abstract

For more effective oncological management of disseminated colorectal cancer, therapies must be devised that target the different individual stages of metastasis development. Recent work showed that integrin subunits alpha2, alpha6 and beta4 are involved in the colorectal cancer cell extravasation process. By means of Immunocytochemistry and Western blotting, it was shown that all three integrins are expressed not only in human colorectal cancer cells (HT29) but also in rat colonic cancer cells (DHDK12). Using in vivo models and intravital video microscopy techniques, it was shown that functional blocking of these integrin subunits by specific antibodies produced a significant reduction in cancer cell extravasation and migration. In conclusion, integrin subunits alpha2, alpha6 and beta4 are expressed in unrelated colorectal cancer cell strains and appear to play a key role in cancer cell migration.

Structural ECM components in the premetastatic and metastatic niche

“…Treatment with an ␣4-blocking antibody reduced macrophage adhesion to LM2 cells, resulting in loss of protection from apoptosis (14). Furthermore, functional blocking antibodies against integrin subunits ␣2, ␣6, and ␤4 reduced extravasation and migration of a set of colorectal cancer cell lines in in vivo models (100). The idea to target and disrupt the adhesion and extravasation process between circulating tumor cells, immune cells, and endothelial cells could potentially prevent distant metastasis from occurring altogether.…”

CD49f-positive cell population efficiently enriches colon cancer-initiating cells

“…We also assessed CD49f and CXCR4 expression, because CD49f was reported as a marker of breast (34), prostate (35) and glioblastoma (36) CSCs and CXCR4 was reported to be a marker of pancreas CSCs (12). CD49f and CXCR4 is also known to deeply associate with cancer metastasis (12,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The expression of CD44 was drastically reduced by NaBT treatment (rate of change, -99.2% in HT29 and -97.2% in Caco2; average, -98.2%).…”

“…In our previous report (31) CD49f, also known as integrin α6 (ITGA6), is a major laminin receptor and mediates cell adhesion (16,18,19,21). In colon cancer, expression of CD49f has been reported to be associated with tumor cell invasion and metastasis via integrin-mediated cell signaling and adhesion to the extracellular matrix (16,18,19,21). CSCs in various cancers show high metastatic potency (12)(13)(14)(15).…”

“…In the liver metastasis model of CRC cells, it is reported that α6-integrin expression on circulating CRC cells mediates cell adhesion in hepatic microcirculation and extravasation into liver parenchyma (18). In addition, inhibition of CD49f by specific antibody resulted in reduction of cancer cell extravasation and migration (21). Successful targeting of CD49f-expressing cells may contribute to the development of a novel radical cancer treatment.…”

“…The assessment of markers for cancer cell metastasis might also be important for the study of CSC in CRC. CD49f, also known as integrin α6 (ITGA6), is reportedly associated with tumor cell invasion and metastasis in CRC (16)(17)(18)(19)(20)(21). The chemokine receptor CXCR4 plays a critical role in cancer cell metastasis via stromal interaction and hypoxia-related pathways (12,(22)(23)(24)(25)(26).…”