Journal of Cytokine Biology
Open Access

The tumor microenvironment (TME) is a complex, dynamic landscape that not only includes malignant cells but also a variety of non-cancerous cells, extracellular components, and signaling molecules. Among the non-cancerous cellular components, fibroblasts play a pivotal role in shaping the TME. These cells are key regulators of the extracellular matrix (ECM), a network of proteins and glycoproteins that provides structural support and regulates cell behavior. In normal tissues, fibroblasts help maintain tissue architecture and support wound healing. However, in the context of cancer, fibroblasts become cancer-associated fibroblasts (CAFs), and they interact with the ECM in ways that can drive tumor progression, metastasis, and resistance to therapy [1].

Fibroblasts and the ECM are intimately involved in tumor microenvironment remodeling, a process that supports tumor growth, invasion, and immune evasion. By altering the ECM composition and cellular signaling, fibroblasts contribute to a tumor-promoting environment that not only supports cancer cell survival but also aids in immune escape and therapy resistance. This article explores the role of fibroblasts and the ECM in tumor remodeling, how this impacts cancer progression, and the potential therapeutic strategies targeting these components to improve cancer treatment [2].

Description

Fibroblasts and the tumor microenvironment

Fibroblasts are the most abundant stromal cells in many tissues and are essential for maintaining tissue homeostasis. In the tumor microenvironment, fibroblasts undergo a process of activation that transforms them into CAFs. This transformation is driven by signaling from the tumor cells, immune cells, and the surrounding ECM. CAFs exhibit a wide range of phenotypic changes, including altered gene expression, increased proliferative capacity, and enhanced secretion of ECM components and cytokines [3]. Unlike normal fibroblasts, CAFs contribute to an inflammatory environment that supports tumor growth and metastasis.

CAFs can be divided into different subtypes based on their functional characteristics and molecular markers. These include myofibroblasts, which express α-smooth muscle actin (α-SMA) and exhibit contractile properties, and inflammatory CAFs, which secrete pro-inflammatory cytokines and chemokines [4]. The heterogeneity of CAFs in the TME reflects the complexity of their interactions with cancer cells and other stromal cells, and it has become increasingly clear that different subtypes of CAFs play distinct roles in cancer progression.

Extracellular matrix remodeling

The extracellular matrix (ECM) is a network of macromolecules, including collagen, fibronectin, laminin, and proteoglycans, that surrounds and supports cells. It provides structural scaffolding, influences cell behavior, and mediates signaling between cells and their environment. In healthy tissues, the ECM is tightly regulated, with continuous remodeling occurring during processes like wound healing. However, in cancer, ECM remodeling is dysregulated, and fibroblasts (in their CAF form) are key players in this process [5].

CAFs produce and modify ECM components, changing the composition and stiffness of the tumor stroma. This ECM remodeling promotes tumor cell proliferation, migration, and invasion. For example, collagen deposition, particularly the overproduction of type I collagen, is a hallmark of tumor stroma and contributes to the stiffness of the ECM. This stiffened environment can enhance tumor cell motility, making it easier for cancer cells to invade surrounding tissues and metastasize [6].

In addition to structural changes, CAFs also secrete a variety of proteases, including matrix metalloproteinases (MMPs), that break down ECM components, facilitating tumor cell invasion and metastasis. By remodeling the ECM, CAFs help create paths for tumor cells to migrate through tissues and enter the bloodstream or lymphatic system, enabling metastasis to distant organs.

Furthermore, the ECM is involved in regulating signaling pathways that control cell survival and differentiation. Changes in the ECM composition and stiffness can activate several intracellular signaling cascades, including those mediated by focal adhesion kinase (FAK) and integrin receptors, which can promote cancer cell survival, growth, and resistance to therapy. ECM remodeling also contributes to the formation of tumor blood vessels through angiogenesis, a process that provides tumors with the oxygen and nutrients needed for continued growth [7].

Fibroblast and ecm crosstalk with immune cells

Fibroblasts and the ECM also play important roles in modulating the immune landscape of the tumor microenvironment. CAFs can interact with immune cells, including tumor-associated macrophages (TAMs) and T-regulatory cells (Tregs), and can influence their function. CAFs secrete cytokines and chemokines that can recruit immune cells to the TME. However, this immune recruitment is often skewed toward the promotion of immune suppression rather than activation. For instance, CAFs can promote the accumulation of immunosuppressive cells like Tregs, which dampen the anti-tumor immune response. The ECM itself can also impact immune cell function. The stiffened ECM can create physical barriers that prevent immune cells from infiltrating tumors effectively. In some cases, the ECM can even induce immune cell dysfunction, making it harder for the immune system to mount an effective response against the tumor.

Conclusion

Fibroblasts and the extracellular matrix play a central role in the remodeling of the tumor microenvironment, driving cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) are key mediators of ECM remodeling, altering its composition and stiffness in ways that support tumor growth, invasion, and immune evasion. Through the secretion of ECM components, proteases, and cytokines, CAFs create an environment that facilitates tumor cell survival and metastasis while also suppressing the immune response. The dynamic interaction between fibroblasts, ECM, and immune cells is essential for understanding how tumors grow and spread. Given the significant role that fibroblasts and ECM remodeling play in tumor progression, targeting these components holds great therapeutic potential. Strategies to target CAFs, either by inhibiting their activation or by blocking their ability to remodel the ECM, could help disrupt the tumor-supportive environment. Additionally, immune-based therapies aimed at reversing immune suppression or increasing immune cell infiltration into the tumor could be enhanced by targeting the fibroblasts and ECM. Despite the promise of these approaches, challenges remain, including the heterogeneity of CAFs and the complexity of ECM remodeling in different tumor types. Nevertheless, continued research into the molecular mechanisms underlying fibroblast activation and ECM remodeling will provide new opportunities to develop targeted therapies that can improve cancer treatment outcomes and prevent metastasis.

Acknowledgement

None

Conflict of Interest

None

1. Warnock JN, Al-Rubeai M (2006) Bioreactor systems for the production of biopharmaceuticals from animal cells. Biotechnol Appl Biochem 45: 1-12.

Indexed at, Google Scholar, Crossref

2. Harding MW, Marques LLR, Howard RJ (2009) Can filamentous fungi form biofilms? Trends Microbiol. 17: 475-480.

Indexed at, Google Scholar, Crossref

3. Kobayashi M, Shimizu S (2000) Nitrile hydrolases. Curr Opin Chem Biol. 4: 95-102.

Indexed at, Google Scholar, Crossref

4. Murphy CD (2012) The microbial cell factory. Org Biomol Chem. 10: 1949-1957.

Indexed at, Google Scholar, Crossref

5. Li XZ, Hauer B, Rosche B (2007) Single-species microbial biofilm screening for industrial applications. Appl Microbiol Biotechnol. 76: 1255-1262.

Indexed at, Google Scholar, Crossref

6. Li Q (2020) Application of Fragment-Based Drug Discovery to Versatile Targets. Front Mol Biosci 7: 180.

Indexed at, Crossref, Google Scholar

7. Ayotte Y,  Murugesan JR,  Bilodeau F, Larda S, Bouchard P, et al. (2017) Discovering Quality Drug Seeds by Practical NMR-based Fragment Screening. Protein Sci 26: 194-195.

Google Scholar