Fibroblasts are common cells found throughout the body’s connective tissues. Their primary function in healthy tissue involves producing the extracellular matrix (ECM), a complex network of proteins and other molecules that provides structural support and acts as a scaffold for cells. These cells also play a part in tissue repair, particularly during wound healing, by synthesizing components like collagen and elastin. Within the context of cancer, these normal fibroblasts can undergo significant changes, transforming into what are known as cancer-associated fibroblasts (CAFs), which are a substantial component of the tumor’s surrounding environment.
The Origin and Activation of CAFs
Cancer-associated fibroblasts primarily arise from normal fibroblasts within the local tissue surrounding a tumor. Cancer cells release signaling molecules and growth factors that reprogram these resident fibroblasts. This transformation causes fibroblasts to adopt new characteristics and functions that support tumor growth.
Other cell types also contribute to the CAF population, including pericytes, smooth muscle cells, adipocytes, and bone marrow-derived mesenchymal stem cells, which migrate to the tumor site and differentiate into CAFs. This diverse origin highlights the tumor’s ability to recruit and transform various stromal cells into its supportive network. Once activated, CAFs exhibit altered gene expression and increased contractile properties compared to their normal counterparts.
How CAFs Remodel the Tumor Environment
Cancer-associated fibroblasts extensively reorganize the tumor’s physical surroundings. They primarily increase the production and deposition of extracellular matrix components, such as collagen, fibronectin, and proteoglycans. This excessive deposition creates a dense, stiff network around cancer cells, forming a protective barrier and a scaffold that supports tumor expansion.
The remodeling by CAFs also involves altering the physical properties of the tissue, leading to increased stiffness. This stiffened environment promotes cancer cell growth and invasion by providing mechanical cues. Additionally, CAFs secrete enzymes, such as matrix metalloproteinases (MMPs), which break down existing ECM components. This allows for continuous reorganization of the matrix and creates pathways for tumor cell movement. This reshaping of the tumor microenvironment benefits tumor survival and progression.
The Role of CAFs in Cancer Progression and Spread
Cancer-associated fibroblasts actively fuel tumor progression through various signaling mechanisms. They release growth factors, such as platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF), promoting cancer cell multiplication and survival. This direct stimulation contributes to tumor growth.
CAFs also play a role in angiogenesis, the formation of new blood vessels that supply the tumor with oxygen and nutrients. They achieve this by secreting pro-angiogenic factors like vascular endothelial growth factor (VEGF), which signals endothelial cells to form new capillaries. Furthermore, CAFs secrete enzymes that degrade surrounding tissue barriers, creating channels that allow cancer cells to detach from the primary tumor and move into the bloodstream or lymphatic system. This process facilitates metastasis, the spread of cancer cells to distant organs.
The Impact of CAFs on Cancer Treatment
Cancer-associated fibroblasts significantly interfere with the effectiveness of cancer treatments. The dense, collagen-rich extracellular matrix produced by CAFs acts as a physical barrier, impeding chemotherapy drugs from penetrating the tumor mass. This obstruction prevents therapeutic agents from reaching target cancer cells in sufficient concentrations, reducing treatment efficacy.
Beyond physical barriers, CAFs secrete soluble factors that protect cancer cells from anti-cancer therapies. These factors induce drug resistance, making cancer cells less susceptible to the cytotoxic effects of chemotherapy and radiation.
CAFs also contribute to an immunosuppressive environment within the tumor. They release molecules like transforming growth factor-beta (TGF-β), which can hinder immune cells, such as T-cells, preventing them from recognizing and destroying cancer cells. This suppression of the immune response reduces the effectiveness of immunotherapies.
Therapeutic Strategies Targeting CAFs
Given their extensive involvement in tumor progression and treatment resistance, cancer-associated fibroblasts are promising targets for new therapeutic strategies. One approach involves directly eliminating CAFs from the tumor microenvironment. This aims to dismantle the supportive scaffold and reduce the pro-tumorigenic signals they provide.
Another strategy focuses on reprogramming CAFs, attempting to revert them to a more normal, quiescent fibroblast state. This would neutralize their harmful functions without destroying them. Researchers are also exploring ways to block the pro-cancer signals that CAFs send to tumor cells, disrupting the communication pathways that fuel cancer growth and spread. These therapeutic avenues aim to improve existing treatments by disrupting the tumor’s supportive environment and making cancer cells more vulnerable to therapy.