International Journal of Inflammation, Cancer and Integrative Therapy
Open Access

Obesity has become a global health epidemic, with an increasing number of individuals affected by this condition. Beyond its well-known association with metabolic disorders like type 2 diabetes and cardiovascular diseases, obesity is now recognized as a major risk factor for the development and progression of various cancers. One of the key mechanisms through which obesity contributes to cancer is chronic, low-grade inflammation, which is induced by excess adipose (fat) tissue. This obesity-driven inflammation can alter the tumor microenvironment, promote tumorigenesis, and influence cancer progression. As a result, understanding the link between obesity, inflammation, and cancer is crucial for developing new preventive and therapeutic strategies. This article explores how obesity-induced inflammation contributes to cancer development and progression, the key mechanisms involved, and potential approaches for targeting this pathway to reduce cancer risk [1].

Description

The link between obesity and inflammation

Obesity is characterized by the accumulation of excess adipose tissue, particularly visceral fat, which is located around internal organs. Unlike subcutaneous fat, visceral fat is metabolically active and secretes a wide range of bioactive molecules, including hormones, cytokines, and adipokines, that can trigger inflammatory responses. In a normal, healthy state, inflammation is a short-term, protective immune response to injury or infection. However, in obesity, the persistent overproduction of pro-inflammatory molecules leads to chronic, low-grade inflammation.

The key features of obesity-related inflammation include:

Adipocyte hypertrophy: In obese individuals, adipocytes (fat cells) become enlarged as a result of the increased storage of fat. This hypertrophy can lead to cellular stress, which triggers an inflammatory response. The stressed adipocytes release inflammatory cytokines such as TNF-α, IL-6, and IL-1β, which recruit immune cells to the site of inflammation.

Macrophage infiltration: Obese adipose tissue is infiltrated by macrophages, immune cells that play a critical role in the inflammatory response. In healthy adipose tissue, macrophages are typically present in low numbers and are involved in tissue repair [2]. However, in obesity, the number of macrophages significantly increases, and they adopt a pro-inflammatory (M1) phenotype. These macrophages release additional cytokines and chemokines, further amplifying inflammation and contributing to systemic metabolic dysfunction.

Adipokine imbalance: Adipocytes release adipokines, which are signaling molecules that regulate metabolic functions. In obesity, the balance of adipokines is disrupted, with an overproduction of pro-inflammatory adipokines like leptin and resistin, and a decrease in anti-inflammatory adipokines such as adiponectin. Leptin, in particular, has been shown to promote the activation of inflammatory pathways, including NF-κB and JAK-STAT, which play crucial roles in tumor promotion.

Endoplasmic reticulum (ER) stress: Excessive fat storage in adipocytes leads to the accumulation of unfolded proteins in the endoplasmic reticulum, a condition known as ER stress. ER stress activates the unfolded protein response (UPR), which can induce inflammatory pathways and contribute to chronic inflammation.

The chronic, low-grade inflammation associated with obesity leads to systemic metabolic disturbances and affects multiple organs and tissues, including the immune system. This creates a pro-tumor microenvironment that promotes cancer development [3].

Obesity-driven inflammation and cancer development

Obesity-induced inflammation plays a central role in the initiation and progression of various cancers. The inflammatory environment in obese individuals promotes cellular processes that are critical for cancer development, including cell proliferation, survival, angiogenesis, immune evasion, and metastasis. The key mechanisms through which obesity-driven inflammation contributes to cancer include:

Activation of pro-inflammatory signaling pathways: In obesity, several pro-inflammatory signaling pathways are activated that contribute to tumorigenesis. These include the NF-κB pathway, which regulates the expression of inflammatory cytokines, and the JAK-STAT pathway, which controls immune responses and cell survival. Dysregulation of these pathways in adipose tissue and tumor cells promotes cell proliferation, inhibits apoptosis, and enhances the angiogenic potential of tumors.

Insulin resistance and hyperinsulinemia: Obesity often leads to insulin resistance, a condition in which the body’s cells become less responsive to insulin. As a result, the body compensates by producing higher levels of insulin. Elevated insulin levels can promote the growth and survival of cancer cells by activating the insulin/insulin-like growth factor (IGF) pathway, which is involved in cell proliferation and tumor progression. Hyperinsulinemia also contributes to chronic inflammation by increasing the production of pro-inflammatory cytokines [4].

Adipose tissue-derived cytokines and tumor progression: The chronic inflammation in obese individuals is characterized by the overproduction of adipokines and cytokines such as TNF-α, IL-6, and leptin. These molecules can directly promote cancer cell growth and survival. For example, IL-6 and TNF-α activate the NF-κB and JAK-STAT signaling pathways, leading to increased tumor cell proliferation and resistance to cell death. Leptin has been shown to promote the development of breast, colon, and endometrial cancers by enhancing cell proliferation, migration, and angiogenesis.

Immune suppression in the tumor microenvironment: Chronic obesity-related inflammation leads to immune system dysregulation, which can impair the body’s ability to mount an effective immune response against tumor cells. In obesity, there is an increase in the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which are immune cells that suppress anti-tumor immunity. In addition, the inflammatory cytokines released in the TME can inhibit the function of cytotoxic T cells and natural killer (NK) cells, allowing tumors to evade immune surveillance [5].

Increased angiogenesis and metastasis: The inflammatory environment in obesity promotes the production of angiogenic factors such as vascular endothelial growth factor (VEGF), which enhances blood vessel formation. This facilitates the growth of tumors by providing them with the nutrients and oxygen required for expansion. Inflammation also promotes the expression of matrix metalloproteinases (MMPs), enzymes that break down the extracellular matrix and allow cancer cells to invade surrounding tissues and metastasize.

Obesity and cancer progression

In addition to promoting cancer initiation, obesity-driven inflammation accelerates cancer progression and worsens prognosis. The inflammatory microenvironment in obese individuals fosters tumor cell growth, metastasis, and resistance to therapy. Moreover, inflammation-induced alterations in the immune response create an environment that supports tumor survival and immune evasion, contributing to the failure of immune-based therapies. Some ways in which obesity influences cancer progression include:

Resistance to chemotherapy: Chronic inflammation associated with obesity can promote resistance to chemotherapy by inducing DNA damage repair mechanisms, suppressing apoptosis, and increasing the survival of cancer cells. Moreover, obesity-induced alterations in the tumor vasculature can lead to inefficient drug delivery, further hindering the effectiveness of chemotherapy [6].

Resistance to immunotherapy: The immune suppressive effects of obesity-related inflammation can limit the effectiveness of immunotherapies, including immune checkpoint inhibitors. By promoting immune evasion, chronic inflammation reduces the ability of the immune system to recognize and destroy tumor cells, making immunotherapy less effective.

Increased risk of recurrence: Obesity-driven inflammation not only contributes to the initial development of cancer but also increases the risk of cancer recurrence. The inflammatory environment supports the survival of residual cancer cells and promotes the formation of secondary tumors, which can lead to relapse and metastasis.

Conclusion

Obesity is a major risk factor for cancer, with inflammation playing a central role in the development and progression of obesity-related malignancies. Chronic low-grade inflammation caused by excess adipose tissue creates a pro-tumor microenvironment that promotes cancer initiation, progression, metastasis, and resistance to treatment. Key mechanisms include the activation of pro-inflammatory signaling pathways, insulin resistance, immune suppression, and increased angiogenesis. As the global prevalence of obesity continues to rise, understanding the link between obesity-driven inflammation and cancer is crucial for developing effective strategies to prevent and treat obesity-related cancers. Therapeutic approaches that target inflammation, reduce adiposity, or modulate the immune response may help mitigate the cancer-promoting effects of obesity and improve patient outcomes.

Acknowledgement

None

Conflict of Interest

None

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