Extracellular matrix: unlocking new avenues in cancer treatment

Abstract

The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.

Keywords: Cancer; Cancer resistance; Extracellular matrix; Tumor microenvironment.

Fig. 1

A comparison of the ECM and vessel density between the normal microenvironment and the TME highlights significant differences driving cancer progression. Angiogenesis, the formation of new capillaries, supplies tumors with the blood necessary for their survival and growth. As a structural component of the TME, the ECM plays an essential role in tumor development and progression. The transition from a normal microenvironment to a TME involves several key changes, including an altered cellular composition marked by increased proliferation of cancer cells, cancer-associated fibroblasts, and reprogrammed immune cells. The TME becomes more degraded, facilitating tumor invasion, while abnormal angiogenesis results in poorly structured blood vessels, leading to hypoxia and acidosis. These conditions, combined with altered metabolic processes like the Warburg effect, support rapid tumor growth. Furthermore, immune cells within the TME are often suppressed, enabling tumors to evade immune surveillance. Chronic inflammation within the TME further accelerates tumor progression. (Created with BioRender.com)

Fig. 2

Collagen plays a critical role in the development and progression of various tumors by influencing tumor behavior through multiple signaling pathways and cytokines. Collagen expression is frequently upregulated in many cancers, and this elevated expression often serves as an independent risk factor for reduced overall survival across different cancer types. For example, type XI collagen (COL11A1) significantly impacts the prognosis of breast cancer patients by modulating the immune cell infiltration within tumors. Malignant tumors also exhibit greater stiffness compared to benign tumors, primarily due to the proliferation of connective tissue in the ECM, with COL I being the dominant structural component [5]. Figure adapted from Fig. 2 of Zhang et al. [5]

Fig. 3

An overview of key signaling pathways involved in cellular processes highlights their highly regulated interactions, which coordinate essential cellular functions. In cancer, dysregulation or aberrant activation of these pathways is frequently observed, contributing to metastasis, resistance, and other complications. Understanding these pathways offers valuable insights into novel therapeutic strategies that target specific cellular processes, offering promising treatment options for diseases characterized by uncontrolled cell growth and progression. (Created with BioRender.com)