Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression.

Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal-tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells.

A top-down view of the tumor microenvironment: structure, cells and signaling.

It is well established that the tumor microenvironment (TME) contributes to cancer progression. Stromal cells can be divided into mesenchymal, vascular, and immune. Signaling molecules secreted by the tumor corrupts these cells to create "activated" stroma. Equally, the extracellular matrix (ECM) contributes to tumor development and invasion by forming a biologically active scaffold. In this review we describe the key structural, cellular and signaling components of the TME with a perspective on stromal soluble factors and microRNAs (miRNAs).