Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts

Abstract

Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C–X–C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.

Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression

“…In this study, we determined that NF are spontaneously activated to become α-SMA positive myofibroblasts by gaining a CAF phenotype. The NF differentiation into CAF might be attributed to spontaneous activation due to the intercellular interactions with tumor cells [17,18]. However, Mellone M. et al demonstrated that senescence of NF promotes their differentiation into α-SMA positive myofibroblasts [19].…”

Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Cell Invasion through Integrin β6 Upregulation in Colorectal Cancer

“…Besides direct cell-cell contact, cancer cells can activate fibroblasts to initiate an inflammatory response, promoting the expression of IL-6 [ 30 ]. Multiple growth factors secreted by cancer cells, such as transforming growth factor-beta (TGF- β ) [ 19 ] and platelet-derived growth factors [ 31 ], induce the transformation of fibroblasts. Furthermore, tumor-derived extracellular vesicles (EVs), including exosomes, are involved in tumor-fibroblast communication by transferring principal factors.…”

“…In fact, in regard to the crosstalk of integrin β 6 with paracrine signals, the SDF-1/CXCR4 axis is able to induce directional migration and liver metastasis of CRC cells by upregulating integrin α v β 6 [ 39 ]. On the other hand, integrin α v β 6 of CRC cells activates fibroblasts via TGF- β signaling followed by increased production of SDF-1 from CAFs [ 19 ]. One important characteristic of IL-6 is the persistent activation in the whole process of inflammatory bowel disease and CRC, while the upregulations of other cytokines like TGF- β 1, IL-10, and IL-23 only show up primarily during CRC development [ 38 ].…”

The Biological Functions and Clinical Applications of Integrins in Cancers

“…It is worth noted that tumor cells recruit CAFs and promote their survival by expressing integrins (Peng et al, 2018). Peng et al (2018) showed that integrin avb6 on colon cancer cells induced inactive fibroblasts to become CAFs. Overexpression of integrin a9b1 in breast cancer promoted the recruitment of CAFs (Ota et al, 2014).…”