Organs are composed of functional tissue (parenchyma) and a supporting structure (stroma). Fibrosis is the process of excessive scar tissue formation following injury, which leads to tissue hardening and impaired function. Stromal fibrosis is a non-malignant condition resulting from a prolonged tissue response to damage. However, its presence creates a specific environment that influences the development and spread of malignant disease.
Defining Stromal Fibrosis
The stroma provides the physical framework for an organ and is primarily constructed of the Extracellular Matrix (ECM), a complex scaffold of proteins and carbohydrates. This matrix is built and maintained by specialized cells, predominantly fibroblasts, which reside within the connective tissue. Fibrosis represents a pathological accumulation and reorganization of ECM components, resulting in a dense, stiffened tissue architecture.
Tissue injury initiates this process by triggering resident fibroblasts to transform into activated cells called myofibroblasts. Myofibroblasts express contractile proteins, allowing them to physically remodel the surrounding tissue. They also overproduce ECM proteins, particularly collagen (such as Type I and Type III) and glycoproteins like fibronectin. The overproduction and cross-linking of these proteins increase the tissue’s mechanical stiffness, which disrupts normal organ function.
Chronic fibrosis is defined by the persistence of myofibroblast activity long after the initial injury has resolved. Normally, these cells undergo programmed cell death (apoptosis) once repair is complete. In fibrotic conditions, however, they remain active, continuously depositing a dense and disorganized matrix that leads to permanent scarring.
Common Organ Sites and Initiating Factors
Stromal fibrosis is a common outcome of chronic disease that manifests across many organ systems. The condition typically arises in response to persistent tissue injury or long-term inflammation. This continuous cycle of damage and incomplete repair drives the sustained activation of matrix-producing cells.
Specific high-incidence sites include the liver (hepatic fibrosis), often caused by chronic viral hepatitis, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease (MASLD). Pulmonary fibrosis in the lungs is frequently linked to environmental exposures or autoimmune disorders. Fibrosis also commonly develops in glandular tissues, such as the breast and prostate, often influenced by hormonal signaling or chronic inflammatory states.
Chronic conditions like obesity and diabetes are systemic factors that contribute to fibrotic environments in multiple organs. The sustained stress from these metabolic disorders releases signaling molecules that promote the persistent activation of fibroblasts. The resulting fibrotic tissue alters the normal biology of the entire organ.
Stromal Fibrosis and Cancer Progression
Stromal fibrosis does not typically initiate the genetic mutations that cause malignancy. Instead, it creates a supportive environment that promotes the progression, aggressiveness, and therapeutic resistance of existing cancer cells. This fibrotic area surrounding a tumor is termed the Tumor Microenvironment (TME), and the activated myofibroblasts within it are designated as Cancer-Associated Fibroblasts (CAFs).
Mechanical Signaling
The increased stiffness of the fibrotic ECM acts as a mechanical signal that cancer cells interpret as an instruction to migrate and proliferate. This stiff matrix functions like a rigid scaffold, facilitating the movement of malignant cells and promoting metastasis. Cross-linking enzymes, such as lysyl oxidase (LOX), are often upregulated in fibrotic tissue, further increasing the density and rigidity of collagen fibers. This biomechanical change directs cancer cell behavior, encouraging invasion into surrounding tissues.
Biochemical Signaling
CAFs are master regulators of the TME, releasing signaling molecules that support tumor growth. They secrete growth factors and cytokines, such as Transforming Growth Factor-beta (TGF-β), which stimulates both fibrosis and tumor cell proliferation. This biochemical crosstalk fuels cancer cells, encouraging them to undergo epithelial-to-mesenchymal transition (EMT), making them more mobile and invasive. CAFs also release chemokines, such as CXCL12, which recruit other cell types and enhance the tumor-promoting environment.
Immune Evasion
The dense, fibrotic matrix impedes immune surveillance by creating a barrier that obstructs immune cell access to the tumor site. A high density of collagen can block cytotoxic T cells—the body’s primary anti-cancer defense—from infiltrating the tumor core. Furthermore, CAFs chemically induce an immunosuppressive state within the TME through secreted factors.
CAFs modulate immune cells by releasing cytokines that promote the differentiation of macrophages into the M2-like phenotype, which supports tumor growth and suppresses anti-cancer immunity. This environment shields malignant cells from immune attack, allowing the tumor to grow unchecked. The interaction between CAFs and immune cells establishes a protective niche for the cancer, driving immune evasion and resistance to immunotherapies.