Obesity is a major risk factor for cancer

In the sedentary era, weight gain is becoming a serious preventable risk factor for increased body mass index which strongly correlates with enhanced cancer threat.

Epidemiology

As reported cancers of endometrial, oesophageal adenocarcinoma, colorectal, postmenopausal breast, prostate & renal are caused due to surplus weight.

The mechanism behind obesity and cancer partnership

The body’s lean shape is regulated by the delicate balance between adipocytes & immune cells. Chronic nutrient overload leads to adipocyte hypertrophy, mitochondrial dysfunction, increased oxidative & endoplasmic reticulum stress, proinflammatory signaling, adipokine secretion & cell death. Collectively instigate enhanced secretion of proinflammatory factors, dysregulated systemic metabolism, tumor growth, metastasis & progression.

Changes at the tissue level

• Alteration in an adipose stromovascular fraction.

• Reduction in anti-inflammatory Treg & TH2 cells.

• Increase in proinflammatory TH1 & CD8+T cells.

• Variation in M2 to M1 macrophages.

How adipose-derived factors affect cancer

1. Adipokines - Weight gain alters the interaction between adipocytes and adipokine production.

2. Adiponectin- Obesity triggers adiponectin reduction & causes a mutation in adiponectin receptors (ADIPOR1 & ADIPR2).

3. Leptin -Excessive weight facilitates leptin resistance & hyperlipidemia, and enables cell proliferation, migration, invasion responses, and tumor development.

4. Estrogen- Increased weight fosters adipose-derived aromatase activity, estrogen production, systemic estrogen bioavailability, adipose-derived proinflammatory factors (IL-1β, IL-6, prostaglandin E2, and TNFα), liver-derived insulin growth factor 1 (IGF-1).

5. IL-6 and TNFα- Obesity-induced excess IL- and TNFα levels encourage cellular transformation, proliferation, invasion, angiogenesis, metastasis, cancer cell proliferation, survival & angiogenesis.

6. IL-1β- Heavy weight increases free fatty acid, cholesterol, blood sugar, and free radical levels stimulating tumor expression of IL-1β, NOD-like receptor family, pyrin domain containing 3 (NLRP3) & inflammasome activity.

7. Osteopenia-Neoplastic transformation, cancer cell survival & metastasis progression enhances due to obesity-driven osteopenia phosphoprotein.

8. YKL-40- Excessive obesity with diabetes generates YKL-40, cancer cell proliferation, angiogenesis, and extracellular matrix remodeling.

9. PAI-1- Advancing obesity increases PAI-1 (serine protease inhibitor), cancer cell invasion, metastasis & tumors.

10. Endotrophic -Increased adipose tissue promotes endotrophic production, and activates TGF-β signaling, tumor cell growth & metastasis.

Metabolic dysregulation & life-threatening obesity-related outcomes

• Central obesity causes insulin resistance, dyslipidemia, hyperglycemia & metabolic dysfunction.

• Visceral adipose tissue aggravates the abdominal cavity’s momentum & produces more pro-inflammatory factors.

Effect of Weight loss effect on cancer risk

Weight loss decreases infiltrating macrophages in adipose tissue inflammation, systemic complications of proinflammatory adipokines, obesity-linked pathologies & delays carcinogenesis. Dietary restriction-motivated weight loss reduces colorectal inflammation, decreases rectosigmoid expression of multiple proinflammatory cytokines and markers of T -cell, macrophage accumulation & attenuates cancer pathways (FOS, JUN, STAT3, and NF-κB expression).

Conclusion

Visible weight loss reduces cancer risk, diminishes adipose-related inflammatory mechanisms, and regulates tumor development & progression. Reduction and control of cancer risk demand a better understanding of cellular & molecular mechanisms behind obesity-induced inflammation, the proactive invention of early diagnosis biomarkers & accessible effective cancer therapy.

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