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.
Highlights
Almost 130 years ago, Paget [1] put forth the famous ‘seed and soil’ theory to explain the metastatic preference of cancer cells for specific organs
The results showed that β6 mRNA expression was high in HT-29, Caco-2, Lovo, and SW620 colorectal cancer (CRC) cell lines, with the highest expression observed in HT-29 cells and the lowest expression found in RKO cells (Figure 1A)
The results showed that integrin αvβ6 increased the secretion of stromal cell-derived factor-1 (SDF-1) by cancer-associated fibroblast (CAF), which was decreased upon β6 knockdown by siRNA (**P
Summary
Almost 130 years ago, Paget [1] put forth the famous ‘seed and soil’ theory to explain the metastatic preference of cancer cells for specific organs. The cancer cells were considered the ‘seeds’, and the specific organ microenvironment was the ‘soil’; interactions between the ‘seeds’ and ‘soil’ were proposed to determine the formation of a secondary tumor. The concept of the tumor microenvironment (TME) gradually gained empirical support [2,3]. The TME is composed of many types of cells and proteins, such as fibroblasts, inflammatory cells, immune cells, vascular endothelial cells, mesenchymal stem cells (MSCs), and extracellular macromolecules including collagen, laminin, and protein polysaccharides. The TME does function as a scaffold to support tissue architecture and integrity and secretes cytokines, growth factors, and protease
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