Cancer growth and spread rely heavily on a complex ecosystem known as the tumor microenvironment. This surrounding tissue is a dynamic mix of blood vessels, immune cells, and structural proteins, all interacting with the cancer cells themselves. Among the most abundant and influential non-cancerous components are the fibroblasts, which become activated in response to the tumor. These highly specialized cells are termed Cancer-Associated Fibroblasts (CAFs). CAFs function as the architects and support staff that facilitate disease progression, making their identity and diverse actions necessary for developing effective therapies.
Defining Cancer Associated Fibroblasts: Identity and Origin
Cancer-Associated Fibroblasts are activated versions of normal fibroblasts, the common cells responsible for maintaining the structural integrity of healthy tissue. When triggered by signals from a developing tumor, these cells undergo a phenotypic change, adopting a highly proliferative and contractile state. This activation gives them an altered, elongated morphology, often described as spindle-shaped. They express specific markers, such as alpha-smooth muscle actin (alpha-SMA) and Fibroblast Activation Protein (FAP), which are minimally present in their normal counterparts.
The origins of CAFs are heterogeneous, reflecting the complex nature of the tumor microenvironment. The most common source involves the activation of resident fibroblasts located near the tumor site, often driven by growth factors like Transforming Growth Factor-beta (TGF-beta) released by cancer cells. CAFs can also arise through transdifferentiation, where other non-fibroblast cell types acquire fibroblast-like characteristics. This includes Epithelial-Mesenchymal Transition (EMT) and Endothelial-Mesenchymal Transition (EndMT), transforming epithelial or endothelial cells into activated CAFs.
A third major source is the recruitment of cells from distant areas of the body, particularly bone marrow-derived mesenchymal stem cells (BM-MSCs). These circulating progenitor cells are drawn to the tumor microenvironment by specific chemical signals. Once there, they differentiate into a distinct subpopulation of CAFs. This varied cellular origin contributes to the overall heterogeneity and functional diversity of the stromal compartment.
Structural Roles: How CAFs Reshape the Extracellular Matrix
The primary structural contribution of CAFs involves the massive production and remodeling of the Extracellular Matrix (ECM), the non-cellular scaffolding that provides physical support to tissues. In normal tissue, the ECM is loosely organized. CAFs dramatically alter this architecture by secreting excessive amounts of proteins, mainly Type I collagen and fibronectin (FN1). This uncontrolled deposition leads to desmoplasia, a pathological increase in tissue density and a hallmark of many solid tumors.
This protein overproduction results in a significant increase in the stiffness of the tumor tissue. CAFs also secrete enzymes, such as lysyl oxidase (LOX), which create strong cross-links between collagen fibers, further enhancing matrix rigidity. This mechanical stiffening has profound implications for cancer progression. The dense, fibrotic stroma acts as a physical barrier, impeding the transport and diffusion of anti-cancer drugs, contributing to chemoresistance.
The mechanical forces exerted by CAFs also actively promote tumor cell movement and invasion. CAFs use their contractile machinery to reorganize the ECM, aligning deposited collagen and fibronectin fibers into parallel tracks. These aligned fibers function like structural highways, guiding cancer cells away from the primary tumor mass. CAFs can even physically attach to tumor cells and exert pulling forces, leading a collective invasion out of the primary site.
Functional Roles: CAFs in Tumor Growth and Metastasis
Beyond their structural functions, CAFs operate as the tumor’s communication hub, using a vast array of soluble factors to directly influence malignant cells. They secrete numerous growth factors and cytokines, including Hepatocyte Growth Factor (HGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor-beta (TGF-beta). These factors stimulate tumor cell proliferation and survival in a paracrine manner. CAFs also enhance cancer cell resistance to programmed cell death by releasing Stromal-Derived Factor 1 (SDF-1/CXCL12), which upregulates anti-apoptotic proteins.
CAFs are deeply involved in promoting angiogenesis, the formation of new blood vessels necessary to supply the growing tumor with oxygen and nutrients. They are a significant source of Vascular Endothelial Growth Factor (VEGF), which stimulates vessel growth. CAFs secrete enzymes like matrix metalloproteinases (MMPs) that cleave VEGF and other growth factors trapped within the ECM, releasing them in an active form. They also recruit endothelial progenitor cells to the tumor site, boosting the development of a supportive vasculature.
The involvement of CAFs extends to metastasis and the preparation of distant sites for colonization. CAFs induce the Epithelial-to-Mesenchymal Transition (EMT) in cancer cells through the secretion of factors like TGF-beta and chemokines such as CCL2. This grants tumor cells the motility required for invasion. Before the arrival of cancer cells, CAFs help establish the pre-metastatic niche (PMN) in organs like the lung or liver by releasing Extracellular Vesicles (EVs) and secreted proteins that remodel the distant tissue.
A significant functional role of CAFs is suppressing the anti-tumor immune response, allowing cancer cells to evade detection and destruction. CAFs create an immunosuppressive microenvironment by secreting chemokines like CCL2 and CXCL12, which recruit inhibitory immune cells such as Myeloid-Derived Suppressor Cells (MDSCs) and T regulatory cells (Tregs). These recruited cells actively prevent cytotoxic T cells from attacking the tumor. CAFs also directly inhibit immune cell function through molecules like TGF-beta and Interleukin-6 (IL-6), which suppress T-cell activity and upregulate immune checkpoints like PD-L1.
Targeting CAFs for Cancer Therapy
Given the extensive pro-tumorigenic roles of CAFs, they represent promising targets for novel cancer therapies aimed at dismantling the tumor’s support structure. One strategy involves the direct elimination or depletion of CAFs by targeting the FAP protein, which is highly expressed on their surface. FAP-targeted therapies are currently under investigation. These include chimeric antigen receptor T (CAR-T) cells and radioligand therapy (e.g., FAPI-series), which deliver a toxic payload specifically to the CAF population.
An alternative approach is the functional reprogramming of CAFs, aiming to switch them from a tumor-promoting state to a quiescent or tumor-suppressive state. This involves blocking the signaling pathways that maintain CAF activation, such as TGF-beta signaling, or using agents like Vitamin D analogs to induce their normalization. Reprogramming CAFs is often explored in combination with immune checkpoint inhibitors. Normalizing the microenvironment can enhance T-cell infiltration and boost the effectiveness of immunotherapy.
Another therapeutic focus is disrupting the physical barrier created by the fibrotic ECM. Anti-fibrotic drugs like Nintedanib, which block the fibroblast growth factor receptor family, are studied for their ability to reduce tumor stiffness in desmoplastic cancers. Inhibitors of LOX (such as PXS-5505) can prevent the cross-linking of collagen fibers, softening the tissue. Targeting these structural components and signaling pathways offers a path to overcome treatment resistance by allowing better penetration of chemotherapy and immune cells.