Direct Interaction between Carcinoma Cells and Cancer Associated Fibroblasts for the Regulation of Cancer Invasion

Abstract

The tumor stroma acts as an essential microenvironment of the cancer cells, which includes many different types of non-cancerous cells and the extracellular matrix (ECM). Stromal fibroblasts (SFs) are the major cellular constituents of the tumor stroma and are often called cancer-associated fibroblasts (CAFs). They are often characterized by α-smooth muscle actin (αSMA) expression, which is indicative of the myofibroblast phenotype and strong contractility. These characteristics contribute to the remodeling and stiffening of the stromal ECM, thereby offering an appropriate field for cancer cell invasion. Importance of the tumor stroma in cancer progression has recently been highlighted. Moreover, several reports suggest that stromal fibroblasts interact with adjacent cancer cells through soluble factors, exosomes, or direct cell-cell adhesion to promote cancer cell invasion. In this review, current models of the regulation of cancer cell invasion by surrounding fibroblasts are summarized, including our recent work on the interaction between stromal fibroblasts and scirrhous gastric carcinoma (SGC) cells by using a three-dimensional (3D) culture system. Further mechanistic insights into the roles of the interaction between cancer cells and stromal fibroblasts in cancer invasion will be required to identify novel molecular targets for preventing cancer cell invasion.

Keywords: cancer invasion; cancer-associated fibroblasts; peritoneal dissemination; scirrhous gastric carcinoma.

Figure 1

Direct interaction between cancer-associated fibroblasts (CAFs) and cancer cells promotes cancer cell invasion. CAFs and SGC cells indirectly interact via paracrine signaling mediated by soluble factors and exosomes. This interaction induces phenotypic changes in both the cell types, which in turn trigger cancer cell invasion. Through paracrine signaling, the two cell types attract each other, leading to a direct physical interaction that may be mediated by cell-surface adhesion molecules. This direct interaction may cause further changes in both cell types, resulting in a more efficient CAF-led cancer cell invasion.

Figure 2

Direct interaction between cancer-associated fibroblasts (CAFs) and scirrhous gastric carcinoma (SGC) cells. (A) CAFs and SGC cells cultured at the top of the 3D Matrigel form invasive foci. SGC cells come in contact with CAFs and co-invade the 3D Matrigel; (B) F-actin staining of the invasive foci consisting of CAFs and SGC cells showed that the foci invade the Matrigel and are associated with cleaved signals for collagen type IV; (C) CAFs expressing fibronectin (white arrowheads) physically associate with SGC cells by extending their lamellipodia and filopodia toward SGC cells (yellow arrowheads). The lower panels show magnified images of the boxed regions; (D) Treatment with an Src inhibitor dasatinib blocks the interaction between CAFs and SGC cells, resulting in the suppression of invasive foci formation and invasion. (A and D) Images are reproduced from Yamaguchi et al. [46].