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The obesity pandemic continues to expand on a worldwide basis, as do its associated comorbidities including type 2 diabetes mellitus, cardiovascular disease, and cancer.[1, 2] A major awareness of the association between obesity and an increased incidence and increased risk of death occurred with the publication of the results from the American Cancer Society Cancer Prevention Study II.[3-5] It is now apparent that obesity is associated with an increased incidence of colorectal cancer; esophageal adenocarcinoma; and cancers of the gastric cardia, gallbladder, pancreas, liver, kidney, postmenopausal breast, endometrium, and thyroid as well as non-Hodgkin lymphoma and multiple myeloma, and most likely high-grade prostate and ovarian cancer, and the list continues to grow.[6-9] As an indicator of the magnitude of the problem in the United States, overweight and obesity are associated with a 30% increase in postmenopausal breast cancer; a 2-fold to 4-fold increase in the risk of endometrial cancer; and a relative risk compared with individuals with normal body mass indices (BMIs) of 1.2 to 3.0 for pancreatic cancer, 1.8 to 2.8 for esophageal adenocarcinoma, 1.17 to 1.89 for hepatocellular carcinoma, and 1.15 and 1.46 for colorectal cancer occurring in women and men, respectively.[6, 7]

In addition to the increased risk of cancer associated with obesity, it is also apparent that obesity is associated with an overall poor prognosis and higher death rate, based on all-cause and cancer-associated mortalities.[3, 4] Although many of the cancers found to have a worse prognosis in association with obesity are identical to those found to have a higher incidence, some, such as premenopausal breast cancer, have been shown to have an increased risk of death although not an increased incidence.[10] Overall, the association between overweight and obesity and cancer in the United States is estimated to account for 14% of cancer deaths in men and 20% of cancer deaths in women, whereas maintaining a BMI of < 25 kg/m2 is projected to prevent 90,000 cancer deaths per year.[4, 5]

In terms of incidence and/or prognosis, obesity-associated cancers occurring in the gastrointestinal (GI) tract have expanded from initially including esophageal adenocarcinoma and colorectal cancer to now including gallbladder, pancreatic, gastric cardia, and hepatocellular cancers.[8] The mouse model for intestinal neoplasia, due to a mutation in the adenomatous polyposis coli (APC) gene, results in multiple intestinal tumors, which are predominantly focused within the small intestine and are significantly promoted by obesity.[11-13] Thus, obesity promotes the incidence of malignancies at nearly all levels of the GI tract. In this issue of Cancer, Iyengar et al[14] report the results of a retrospective study of the electronic medical records of 155 patients with oral squamous cell carcinoma (OSCC) of the tongue who were treated at a single institution (Memorial Sloan-Kettering Cancer Center) and demonstrate that patients who were obese at the time of diagnosis were found to have adverse disease-specific survival compared with normal-weight patients (hazards ratio, 2.65; 95% confidence interval, 1.07-6.59 [P = .04]) [Correction made here after initial online publication]. Among patients with prediagnostic weight loss, obese patients were found to have worse overall survival and all-cause mortality compared with normal-weight patients (HR, 2.70; 95% CI, 1.12-6.54 [P = .03]). This is an important observation for several reasons. First, it establishes that the entire GI tract, from beginning to end, can serve as a target for increased obesity-associated cancer incidence and/or increased risk of death. Second, an increased risk of head and neck SCC (HNSCC), as well as its component OSCC, is generally associated with alcohol and tobacco use and considered to be inversely correlated with BMI.[15-17] Likewise, prognosis has generally been associated with quantity of alcohol and tobacco consumption but not obesity.[18] Third, as noted by the authors, the possibility exists that their study was able to identify the obesity association because it was conducted among patients with early-stage T1 and T2 disease, before tumor progression resulted in the onset of weight loss and/or because their study focused on patients with OSCC of the tongue, not all patients with HNSCC.[14] Fourth, and perhaps most interesting, is the association that was noted between obesity and SCC of the tongue, whereas the majority of other obesity-associated GI malignancies are adenocarcinomas.[8] Of particular note in this regard is the association between obesity and a growing incidence of esophageal adenocarcinoma and a decreasing incidence of SCC.[19] In contrast, the newly reported association for obesity is with SCC of the tongue, suggesting that both SCC and adenocarcinomas may have similar response pathways to obesity-mediated promoters.

As suggested by Iyengar et al,[14] having identified the association between obesity and tongue cancer, it is now important to define the mechanism(s) that mediate this relation, because they may provide new opportunities for prevention and therapeutic interventions. Moreover, the possibility of identifying mediators common to both SCC and adenocarcinoma may have even broader implications. However, before examining possible mechanisms and mediators, it is important to consider operational and logistical issues that could impact the interpretation of associations found between obesity and the survival of patients with head and neck cancers. For example, obesity may result in delayed diagnosis and worse prognosis because of patient delay in consulting physicians. Obesity may also limit therapeutic options and may confound the determination of chemotherapy.[20, 21] Although Deneuve et al reported no direct relation between obesity and HNSCC, they noted that obesity interfered with pan-endoscopic evaluation and resulted in missed lymphadenopathy.[18] Obesity also resulted in the greater use of radiotherapy instead of surgery as the more typical primary treatment approach.[18] Despite the potential anatomic and physiologic barriers to examination, endoscopy, anesthesia, and surgery posed by obesity in patients with HNSCC, it is important that they be provided with optimal therapeutic approaches that would be provided for normal-weight patients, as discussed by Deneuve et al.[18] Moreover, it is suggested that these patients follow the recent recommendations from the American Society of Clinical Oncology, indicating that full weight-based calculations be used to determine doses of cytotoxic chemotherapy.[20]

Mechanisms by which obesity is believed to promote cancer, several of which have been alluded to by the authors, generally include: 1) increased sex steroid hormones; 2) increased growth factors, including insulin and insulin-like growth factor 1 (IGF1); 3) altered adipokine levels; 4) low-grade inflammation and cytokines; and 5) altered microbiomes.[5, 7] A brief consideration of these pathways and how they may relate to OSCC of the tongue follows.

Obesity is accompanied by altered levels of sex steroid hormones, including increased estrogens associated with increased aromatase activity in adipose tissue, responsible for converting androgens to estradiol.[5, 7, 22, 23] This pathway is important in promoting postmenopausal breast, uterine, and ovarian cancers,[7] and although the literature regarding a role for sex steroids in HNSCC is sparse and mixed, an important recent study indicated that estrogen stimulates HNSCC growth and invasion in vitro and its effects are further potentiated by epidermal growth factor.[24] Moreover, a role for an estrogen effect in humans is suggested by the observation that women, but not men, with high nuclear estrogen receptor-α levels demonstrated shorter progression-free survival times compared with those with low levels.[24]

Obesity is commonly associated with insulin resistance, hyperinsulinemia, and elevated biologically active IGF1 (increased IGF1 and/or decreased IGF-binding proteins).[2] Elevated insulin and IGF1 acting through the insulin receptor and the phosphatidylinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway promote tumor growth.[7, 25] Because these pathways are known to be active in patients with HNSCC,[26-28] the possibility exists that they could serve as a final channel for the obesity promotion of tongue cancer. Further support for this possibility can be derived from recent studies in OSCC of the tongue in mouse models that demonstrated that metformin, which is commonly used to treat diabetes, may interfere with the growth of SCC of the tongue both in vivo and in vitro.[29, 30] Although these reported studies focused on the intracellular effects of metformin, to our knowledge the systemic insulin-lowering effect has yet to be evaluated.

Adipose tissue secretes multiple important signaling proteins, adipokines, which are related to energy balance control, including adiponectin, which is inversely related to obesity and normally functions along with insulin to regulate glucose metabolism.[7] At normal levels, adiponectin may increase apoptosis and help to control tumor growth, whereas in the presence of obesity, reduced adiponectin levels may have a permissive effect on tumor progression.[7] In contrast, another adipokine, leptin, which normally serves as an appetite suppressant,[7] increases with obesity and has been shown to stimulate tumor growth, especially in breast cancer, in which its effects have recently been shown to be mediated by activation of NANOG, SOX2, and signal transducer and activator of transcription 3 (STAT3), all of which are involved in promoting cancer stem cell growth.[31, 32] Expression of SOX2 and STAT3 has been shown to be synergistic with inflammation in promoting OSCC, thereby providing a potential adipokine-mediated pathway for the promotion of OSCC.[33, 34]

Adipose tissue is now recognized as a source of low-grade cellular- and humoral-mediated chronic inflammation,[35, 36] which is in part the result of the interaction between adipocytes and resident macrophages,[36, 37] resulting in the histologic appearance of crown-like structures; macrophages surrounding dying adipocytes; and the increased release of inflammatory cytokines, prostaglandins, and tumor promoters.[37] It is interesting to note that the Dannenberg laboratory, from which the current study arises, was one of the initial groups to demonstrate the relation between obesity and crown-like structures in patients with breast cancer.[38] Multiple studies have now shown that inflammatory processes, including the stimulation of prostaglandin synthesis pathways, occur in association with resident tumor macrophages in patients with OSCC,[37-42] thereby providing a precedent and pathways for the possibility that obesity-generated inflammation could promote OSCC.

Microflora residing in the GI tract have increasingly been linked to the possibility of malignancy.[43] Helicobacter pylori is associated with gastric malignancy[44] and fusobacteria, found in the mouth, have been implicated in colorectal cancer.[45-48] Because recent studies have shown a significant change in GI microbiota associated with obesity, these observations provide another possible pathway by which obesity may be linked to oral cancer.[49, 50] Any discussion of infectious etiologies of cancer would be incomplete without noting the carcinogenic association between the human papillomavirus (HPV) and anogenital malignancies, including cervical, vulvar, vaginal, anal, and penile cancers,[51, 52] and the more recent demonstration that HPV is associated with OSCC, including oropharyngeal, tonsillar, and base of the tongue cancers.[52-55] Although some of these cancers, including cervical[56] and now tongue cancer,[14] have been associated with obesity, we are not yet aware of reports suggesting an interaction between HPV-induced malignancy and obesity. Nonetheless, because several cancers exist in which each of these factors are associated with an increased relative risk,[57] their potential interaction will require careful epidemiologic, pathologic, and viral surveillance.

The pathways outlined above all provide possible mechanisms by which obesity could promote the growth of and increased risk associated with OSCC. However, although a precedent exists for their involvement, they all remain to be definitively confirmed. Nonetheless, the multiplicity of pathways and the possibility that any one of them could promote SCC of the oral cavity as well as adenocarcinoma elsewhere in the GI tract suggest a principle whereby obesity may promote cancer through preferred pathways, which may exist in tumors of different histologic types and at many different loci.

The expanding list of obesity-associated cancers and the relatively restricted number of pathways involved in mediating these associations emphasize the broad potential benefits and the urgent need for research to develop therapeutic strategies and interventions targeting these obesity-related mediators. In addition, although further research to develop specifically targeted interventions is clearly indicated, it is important to remember that lifestyle changes, including implementation of a moderate diet with an emphasis on plant foods, getting plenty of exercise, avoiding obesity, eliminating tobacco use, and consuming alcohol in moderation, are all highly effective preventative measures.[1, 2, 58]

FUNDING SUPPORT

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  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

The authors made no disclosures.

REFERENCES

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  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES
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