Obesity and cancer

16.1

Overview

• 1.

  Cancer development is stimulated by genetic components, environmental exposures, and lifestyle exposures; all impact the cellular microenvironment and initiate carcinogenesis.

• 2.

  Links between obesity and cancer have been documented for hormonally influenced cancers such as endometrial and breast cancer, and links to broader cancers are emerging.

• 3.

  Changes to systemic and microenvironment from obesity and hypernutrition not only cause significant risk for carcinogenesis but also impact the success and outcome of treatment.

• 4.

  BMI >40 kg/m ² has a 1.6-fold higher risk of cancer death.

• 5.

  The growing epidemic of cancers in obese young people (24–29) that have previously predominantly been seen in only the elderly indicate that the need for control of obesity is of key importance to all nations

16.2

Epidemiological evidence for links between obesity and cancer

• 1.

  The following cancers have been linked to obesity with variable, but consistent relationships:

  • a.

    oesophageal (with greater increases for higher BMI)

  • b.

    gastric

  • c.

    liver

  • d.

    kidney (renal cell)

  • e.

    pancreatic

  • f.

    colorectal

  • g.

    gallbladder

  • h.

    multiple myeloma

  • i.

    meningioma

  • j.

    potentially some thyroid and ovarian cancers.

• 2.

  Study of colorectal cancer risk shows a link to increased risk for colon, but not rectal cancer, based on waist circumference.

• 3.

  Clear differences for risk of different cancer types exist in different genders.

• 4.

  Obesity as a unique risk factor for the development of cancer differs by site.

• 5.

  The International Agency for Research on Cancer working group on Body Fatness in 2016 noted sufficient evidence for links between obesity and postmenopausal breast, colon, endometrial, oesophageal, gallbladder, kidney, liver, meningioma, multiple myeloma, ovary, pancreas, stomach, and thyroid cancer.

• 6.

  Others have proposed links between advanced prostate cancer, mouth, pharynx, and larynx, although the relationship is less clear.

16.3

Cancers unique to or more common in women

• 1.

  50% of endometrial cancer is associated with obesity, with also a striking dose/response curve from 1.5-fold increase for overweight women to 7.1-fold increase for class 3 obesity.

• 2.

  Primary mechanism likely linked to increase in aromatase, conversion of androgens to oestrogens, and then the hormonal influence on proliferation of endometrial cells.

• 3.

  Other mechanisms proposed for nongynecological cancers may also play a role, such as chronic inflammation and production of inflammatory cytokines, increases in insulin-like growth factors, and their associated cellular and genetic impacts.

• 4.

  Weight reduction decreases the risk as show by the use of bariatric surgery.

• 5.

  Breast cancer also shows a strong association with obesity.

• 6.

  Women’s Health Initiative Clinical Study population shows increased risk for invasive breast cancer for overweight and above women compared to normal-weight women with the highest risks in those with grade 2 and 3 obesity.

• 7.

  Dose–response relationship was found again like endometrial cancer.

• 8.

  Also, primarily in hormone receptor positive disease cell types.

• 9.

  However, obese women who lost weight did not have a drop in risk unlike the impact seen with endometrial cancer and bariatric surgery.

• 10.

  When obesity most impacts the risk of breast cancer is unclear.

• 11.

  Obesity during trial may have been lifelong, and thus results reflect critical windows at reproductive age or earlier childhood as well.

• 12.

  Premenopausal obese women may actually have a protective effect from the body fat and decreased risk in that life stage.

• 13.

  Obesity in adolescence during breast development or premenopausal as an impact to risk factor compared to postmenopausal is difficult to study but important to understand for prevention.

• 14.

  High body fat proportions even in normal BMI may increase breast cancer risk.

• 15.

  Type and distribution of body fat is an area of intensive research and may hold keys to future prevention strategies.

16.4

Potential mechanisms for oncogenesis

• 1.

  Many potential pathways are engaged and could result in carcinogenesis with obesity.

• 2.

  Markers of disturbance of the microenvironment such as insulin resistance and inflammation may be more accurate risk predictors than BMI alone.

• 3.

  So too may waist-hip ratios as well as BMI.

• 4.

  Associated conditions, like metabolic syndrome and diabetes have significant impact on outcomes in breast cancer. However, mechanisms underpinning this relationship are still obscure.

• 5.

  Cross talk between adipocytes and macrophages is of particular interest as molecular mechanisms have been associated with adipocyte–macrophage breast cancer cell clusters.

• 6.

  Another component of the altered inflammatory environment may come from inhibition of natural killer cell activity. Further research on pathways in this area may provide additional avenues for cancer treatment specific to obesity-linked cancers.

• 7.

  Type and location of adipose deposits also play a role in hormones and cytokines secreted.

• 8.

  Association of increasing fat mass and increasing fasting insulin levels and hyperinsulinaemia implicates insulin as well as oestradiol as an important biologic link associating trunk adiposity with breast cancer risk.

• 9.

  Body composition rather than simply BMI has been highlighted as of great importance.

• 10.

  High body fat levels associated with elevated levels of insulin, CRP, IL-6, leptin, and triglycerides, as well as lowered high-density lipoprotein cholesterol and sex hormone-binding globulin.

• 11.

  Functional causal mechanisms supported by obesity may differ between locations with chronic secretion and inflammation being posited for the elevation of gallbladder cancer risks, reflux oesophagitis and inflammation for oesophageal cancer risk, associated hypertension with renal cancer risk, and endogenous oestrogen with breast and endometrial cancer risks.

• 12.

  Ultimately actions affecting oncogenesis are carried out at a cellular level with inflammatory mechanisms a common component.

• 13.

  One pathway comes through the downstream influence of increased aromatase activity and stimulation from circulating oestrogens, as noted previously with visceral fat.

• 14.

  Varying pathways interact and other downstream linkages between obesity and cancer are being explored to tease out critical interactions including those leading to insulin resistance.

• 15.

  One characteristic of the obesity–cancer relationship appears to be the significant ongoing cross talk between adipose tissue components, their products, and the cancer cells themselves, leading to a microenvironment that not only promotes carcinogenesis but also promotes metastasis.

• 16.

  Possibly the more disturbed the environment is with insulin resistance and the more exposure to growth-promoting secretome of adipocytes, the more aggressive and potentially metastatic the resulting tumour.

• 17.

  Genes are emerging as potential bridges between obesity and cancer; research is needed to fully explore the gene regulation of the various components involved.

16.5