Collagen in tumor microenvironment
Collagen in tumor microenvironment Collagen, the most abundant protein in the human body, plays a vital role not only in maintaining the structural integrity of tissues but also in influencing numerous biological processes within the tumor microenvironment (TME). The TME is a complex network comprising cancer cells, stromal cells, immune cells, blood vessels, and the extracellular matrix (ECM). Collagen is a critical component of the ECM, shaping the physical and biochemical landscape in which tumors develop and progress.
In the context of cancer, collagen’s role is multifaceted and often paradoxical. On one hand, a dense collagen matrix can act as a physical barrier, hindering the penetration of therapeutic agents and immune cells into the tumor, thereby facilitating tumor growth and metastasis. On the other hand, alterations in collagen composition and organization can influence tumor cell behavior, such as promoting invasion and migration. The stiffness of the collagen network often correlates with tumor aggressiveness; increased collagen cross-linking leads to a stiffer matrix, which can enhance mechanotransduction signals that promote malignant transformation.
Tumor-associated fibroblasts (TAFs) are key players within the TME that modulate collagen production and remodeling. These cells can produce excessive collagen, contributing to desmoplasia—a fibrotic response characterized by abundant collagen deposits. This fibrotic stroma not only supports tumor growth but also creates hypoxic conditions, further driving malignant progression. Moreover, the dynamic remodeling of collagen by matrix metalloproteinases (MMPs) allows tumors to invade surrounding tissues by degrading and reorganizing the ECM. This remodeling process is finely balanced; excessive degradation can facilitate metastatic dissemination, whereas abnormal collagen deposition can hinder immune cell infiltration.
Collagen also interacts with immune components within the TME. Certain collagen fragments serve as signaling molecules that can modulate immune responses, either suppressing or stimulating immune activity. For instance, some collagen-derived peptides have immunosuppressive properties, aiding tumors in evading immune
surveillance. Conversely, targeting collagen or its remodeling enzymes has emerged as a therapeutic strategy to enhance immune infiltration and improve the efficacy of immunotherapies.
Recent advances in imaging and molecular techniques have allowed researchers to better understand collagen’s spatial distribution and its mechanical properties within tumors. These insights highlight the potential for developing therapies that modulate collagen synthesis, cross-linking, or degradation. Agents that soften the ECM or inhibit collagen cross-linking enzymes, such as lysyl oxidase (LOX), are being investigated to improve drug delivery and immune cell infiltration. Additionally, combining ECM-targeting therapies with conventional treatments holds promise for overcoming resistance mechanisms driven by the tumor stroma.
In summary, collagen within the tumor microenvironment is a dynamic and influential component that governs tumor progression, metastasis, and therapeutic response. Understanding the complex interplay between collagen and other TME elements offers valuable opportunities for developing innovative strategies to combat cancer more effectively.
