International Journal of Inflammation, Cancer and Integrative Therapy
Open Access

Cancer metastasis, the spread of cancer cells from a primary tumor to distant organs, remains one of the most significant challenges in cancer treatment. Metastasis is a complex, multi-step process that involves tumor cell invasion, survival in the bloodstream, and colonization of distant tissues. While much of the focus on cancer treatment has been on targeting the tumor cells themselves, there is growing recognition of the critical role that the tumor microenvironment (TME), particularly its inflammatory components, plays in driving metastasis. The TME is a dynamic and heterogeneous milieu composed of cancer cells, immune cells, fibroblasts, endothelial cells, and extracellular matrix components. Chronic inflammation within the TME not only promotes tumor progression but also facilitates the metastasis of cancer cells by altering cell behavior and creating a conducive environment for spread. This article explores the mechanisms through which the inflammatory microenvironment influences cancer metastasis and discusses potential therapeutic strategies to target inflammation for cancer treatment [1].

Description

The inflammatory microenvironment in cancer

The inflammatory microenvironment of tumors is characterized by the persistent activation of the immune system in response to tumor cells, cellular stress, and tissue damage. Under normal conditions, inflammation acts as a protective response to injury or infection, helping the body to repair damaged tissues. However, when inflammation becomes chronic, it can turn pathological and contribute to tumorigenesis and metastasis. The key components of the inflammatory microenvironment include immune cells (e.g., macrophages, neutrophils, T cells), pro-inflammatory cytokines, growth factors, chemokines, and extracellular matrix (ECM) remodeling enzymes. These components work in concert to create an environment that favors tumor cell survival, migration, and invasion [2].

Immune cells in the inflammatory tumor microenvironment: Immune cells, particularly tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and neutrophils, are central players in the inflammatory TME. TAMs are recruited to the tumor site by pro-inflammatory signals, where they can adopt a pro-tumorigenic phenotype. These macrophages secrete cytokines like IL-6, TNF-α, and growth factors such as vascular endothelial growth factor (VEGF), which promote angiogenesis, cell proliferation, and survival. TAMs also produce matrix metalloproteinases (MMPs), which degrade the ECM and facilitate tumor cell invasion and migration. [3]

Similarly, MDSCs are known to suppress anti-tumor immunity and promote an immunosuppressive environment, allowing cancer cells to evade immune detection. Neutrophils, while part of the innate immune system's first line of defense, can also promote metastasis in certain cancers by releasing proteolytic enzymes and inflammatory cytokines that break down the ECM and enhance tumor cell movement.

Cytokines and chemokines in cancer metastasis: Chronic inflammation in the TME leads to the secretion of numerous pro-inflammatory cytokines and chemokines that can support metastasis. For instance, IL-6 is a critical mediator of the inflammatory response, contributing to the activation of signal transducer and activator of transcription 3 (STAT3), which induces the expression of genes associated with tumor cell survival, invasion, and metastasis. IL-1β and TNF-α also promote tumor progression by enhancing cell migration and supporting an environment conducive to angiogenesis [4].

Chemokines, such as CCL2 and CXCL8, attract immune cells to the TME and also regulate the migration of cancer cells. The interactions between cancer cells and immune cells within the TME, guided by these cytokines and chemokines, create a microenvironment that fosters tumor cell dissemination to distant organs.

Extracellular matrix remodeling and cancer metastasis:Inflammation-induced ECM remodeling is another crucial mechanism by which the inflammatory microenvironment promotes metastasis. Cancer cells secrete pro-inflammatory factors that stimulate fibroblasts to produce collagen, fibronectin, and other ECM components, which, in turn, alter the physical structure of tissues and enable tumor cells to invade and migrate [5]. Additionally, the activation of MMPs by inflammatory mediators further breaks down the ECM, providing cancer cells with the necessary space to invade surrounding tissues and enter the bloodstream or lymphatic system.

Mechanisms by which inflammation drives cancer metastasis

Angiogenesis and vascular permeability: Inflammation-induced angiogenesis, the process by which new blood vessels form, is a hallmark of cancer progression. Tumors require an adequate blood supply to sustain their growth and provide oxygen and nutrients to rapidly proliferating cells. Inflammatory cytokines such as VEGF and TNF-α stimulate endothelial cells to proliferate and form new blood vessels, enhancing tumor vascularity. These new vessels, however, are often structurally abnormal and more permeable than normal blood vessels, allowing cancer cells to more easily invade the bloodstream and metastasize to distant organs [6].

Immune cell-mediated tumor cell migration: Chronic inflammation leads to the recruitment of immune cells that interact with cancer cells, promoting their ability to migrate and invade other tissues. For example, the recruitment of TAMs to the tumor site facilitates tumor cell intravasation by secreting factors that degrade the ECM and enhance cell motility. Moreover, immune cells such as MDSCs and neutrophils can directly interact with tumor cells, promoting epithelial-mesenchymal transition (EMT), a process that allows cancer cells to acquire migratory and invasive properties [7].

Promotion of epithelial-mesenchymal transition (EMT): Inflammatory cytokines like TGF-β, IL-6, and TNF-α play a significant role in the induction of EMT, a key process in metastasis. EMT enables epithelial cancer cells to lose their adhesive properties, gain motility, and acquire a mesenchymal phenotype that facilitates their invasion into surrounding tissues. Inflammatory signals act as powerful drivers of EMT, thereby increasing the metastatic potential of cancer cells [8].

Immunosuppression in the TME: Chronic inflammation within the TME also leads to the suppression of effective anti-tumor immunity. Immune cells such as Tregs and MDSCs accumulate in response to inflammatory cytokines and exert inhibitory effects on effector T cells and NK cells. This immunosuppressive environment allows cancer cells to evade immune surveillance, facilitating their spread to distant organs. Additionally, the inflammatory mediators produced by immune cells create an immunosuppressive feedback loop that inhibits the activation of the body’s immune defenses.

Therapeutic opportunities to target the inflammatory microenvironment: Targeting the inflammatory microenvironment offers a promising strategy for inhibiting cancer metastasis and improving the effectiveness of existing cancer therapies. Several approaches are being explored to modulate the inflammatory response and its impact on metastasis:

Anti-inflammatory therapies: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as potential adjuncts to cancer treatment. These drugs, which inhibit cyclooxygenase (COX) enzymes, reduce the production of pro-inflammatory prostaglandins and have been shown to decrease tumor progression and metastasis in preclinical studies. Selective COX-2 inhibitors, in particular, have shown promise in reducing metastasis and improving treatment outcomes in some cancers [9].

Immune checkpoint inhibition: Immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, have transformed cancer treatment by enhancing anti-tumor immune responses. However, in the context of chronic inflammation, these therapies often face challenges due to the immunosuppressive microenvironment. Combining immune checkpoint inhibitors with agents that target inflammatory pathways, such as IL-6 or TNF-α, may help overcome these obstacles and improve therapy efficacy.

Targeting tumor-associated macrophages and MDSCs: Therapies that deplete or reprogram TAMs and MDSCs are being actively researched. By shifting TAMs from a pro-tumorigenic phenotype to a more immune-activating phenotype, or by inhibiting the recruitment and function of MDSCs, it may be possible to reverse the immunosuppressive effects of inflammation and enhance the response to other cancer therapies.

Targeting ECM remodeling: Inhibiting the enzymes responsible for ECM remodeling, such as MMPs, is another potential strategy to block metastasis. By preventing the breakdown of the ECM, these therapies could reduce the ability of cancer cells to invade surrounding tissues and enter the bloodstream. Furthermore, targeting the signaling pathways that control ECM production and remodeling may prevent the physical changes in the TME that facilitate metastasis [10].

Conclusion

The inflammatory microenvironment plays a crucial role in driving cancer metastasis by promoting tumor cell invasion, survival, and immune evasion. Chronic inflammation within the TME creates a conducive environment for the spread of cancer cells to distant organs, facilitating the multi-step process of metastasis. By understanding the mechanisms through which inflammation drives metastasis, novel therapeutic strategies that target the inflammatory components of the TME offer significant potential for improving cancer treatment outcomes. Whether through targeting immune cells, inflammatory cytokines, or ECM remodeling, these strategies hold promise for curbing the metastatic spread of cancer and enhancing the effectiveness of existing therapies. As research in this area continues to evolve, it is likely that more effective and personalized therapies will emerge, offering new hope for patients battling metastatic cancer.

Acknowledgement

None

Conflict of Interest

None

1. Banerjee S, Zhang Y, Ali S, Bhuiyan M, Wang Z, et al. (2005) Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res 5: 9064-9072.

Indexed at, Google Scholar, Crossref

2. Han L, Zhang HW, Zhou WP, Chen GM, Guo KJ (2012) The effects of genistein on transforming growth factor-β1-induced invasion and metastasis in human pancreatic cancer cell line Panc-1 in vitro. Chin Med 125: 2032-2040.

Indexed at, Google Scholar, Crossref

3. El-Rayes B, Philip P, Sarkar F, Shields A, Wolff  R, et al. (2011) A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. Invest New Drugs 29: 694-699.

Indexed at, Google Scholar, Crossref

4. Bimonte S, Barbieri A, Palma G, Luciano A, Rea D, et al. (2013) Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer. BioMed Res Intl 810423.

Indexed at, Google Scholar, Crossref

5. Ma J, Fang B, Zeng F, Pang H, Ma C, et al. (2014) Curcumin inhibits cell growth and invasion through up- regulation of miR-7 in pancreatic cancer cells. Toxicol Lett 31: 82-91.

Indexed at, Google Scholar, Crossref

6. Osterman CJ, Lynch J, Leaf P, Gonda A, Ferguson Bennit HR, et al. (2015) Curcumin modulates pancreatic adenocarcinoma cell-derived exosomal function. Plos One 10: e0132845.

Indexed at, Google Scholar, Crossref

7. Tsai C, Hsieh T, Lee J, Hsu C, Chiu C, et al. (2015) Curcumin suppresses phthalate-induced metastasis and the proportion of cancer stem cell (CSC)-like cells via the inhibition of AhR/ERK/SK1 signaling in hepatocellular carcinoma. J Agric Food Chem 63: 10388-10398.

Indexed at, Google Scholar, Crossref

8. Devassy J, Nwachukwu I, Jones PJ (2015) Curcumin and cancer: barriers to obtaining a health claim. Nutrit Rev 73: 155-165.

Indexed at, Google Scholar, Crossref

9. Subramaniam D, Ramalingam S, Houchen C.W, Anant S (2010) Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem 10(5): 359-371.

Indexed at, Google Scholar, Crossref

10. Osterman C, Gonda A, Stiff T, Moyron R Wall N (2016) Curcumin induces pancreatic adenocarcinoma cell death via reduction of the inhibitors of apoptosis. Pancreas 45: 101- 109.

Indexed at, Google Scholar, Crossref