br biomarkers of inflammation and
biomarkers of inflammation and metabolic dysregulation are limited. In particular, given that obesity has been evaluated well as a risk factor for cancer incidence and mortality, the emphasis to date has been on iden-tifying biomarkers of this association in obese individuals. Our finding suggests that chronic inflammation and metabolic dysregulation in nor-mal BMI individuals may substantially increase their risk of cancer mortality.
We observed a robust association between IL-6 and cancer mortality in both obese and non-obese participants after adjusting for socio-demographics, physical activity, and comorbidities. The association be-came attenuated and non-significant, although remained a 2-fold in-creased risk, among normal BMI but not obese individuals when adjusted for behavioral risk factors (smoking, alcohol) and statin use. In contrast, estimates for overweight/obese participants became stron-ger after adjusting for the behavioral risk factors and statin use. We also observed significantly increased cancer mortality risk with higher CRP levels in normal BMI participants in the fully adjusted models. These findings suggest that regardless of BMI, certain markers of inflam-mation influence the risk of cancer mortality. In addition, the results suggest that behavioral factors may explain part of the increased risk as-sociated with IL-6 in individuals with normal BMI but not overweight/ obese, the robust association between CRP and cancer mortality risk in normal BMI individuals highlights an important role for chronic inflam-mation. Past studies have also observed independent and significant as-sociations of high levels of IL-6 [28–30], CRP [31–34], and obesity [35–37] with cancer mortality. Our study adds to this body of work by showing that the association between inflammatory biomarkers and cancer mortality varies by BMI. Mechanistically, it has been suggested that a chronic inflammatory microenvironment promotes tumor cell
motility, invasion, epithelial to mesenchymal transition and metastasis which in turn lead to poor prognosis . IL-6 promotes tumorigenesis, angiogenesis, invasiveness, and metastasis, and inhibits apoptosis [29,39]. IL-6 also protects cancer Methylpiperidino pyrazole from therapy-induced DNA dam-age and oxidative stress by facilitating the repair and induction of counter-signaling pathways, thus increasing cancer mortality .
We also found a consistent association between higher resistin, a metabolism biomarker, and increased risk of cancer mortality, but only among participants with normal BMI. This association remained statistically significant after adjusting for behavioral risk factors even though mean resistin was not significantly different by BMI. Thus, the differences in the association between resistin and cancer mortality by BMI may be due to the interaction between resistin and BMI rather than resistin alone. Resistin has been studied as a potential missing link between obesity, chronic inflammation, and cancer  due to its association with increased low-density lipoprotein production and in-flammatory response. A previous study has found a direct association between resistin and cancer mortality , and studies have docu-mented that resistin promotes insulin resistance , chronic low-grade inflammation , and tumor cells adhesion to endothelium-a critical step for metastasis [44,45]. The BMI differences BMI in the assocaition between resistin and risk of cancer mortality may be be-cause obese individuals are more likely to already have chronic inflam-mation, while among individuals with normal BMI who might otherwise be without chronic inflammation, higher resistin levels in-duces chronic inflammation and thus worsen the prognosis of cancer. Lp(a), another metabolism-related biomarker, is involved in cholesterol transport, wound healing and tissue repair-pathways that are co-opted by cancer cells to enhance invasion and metastasis. We did not observe
Fig. 2. Survival probability of cancer patients with A) normal BMI, and B) overweight/obesity by tertiles of IL-6.
Fig. 3. Survival probability of cancer patients with A) normal BMI and B) overweight/obese by tertiles of resistin.
a significantly increased risk of cancer mortality associated with Lp
(a) or adiponectin in the current study, although there was a suggestion of increased risk for adiponectin. Studies with larger sample sizes may be needed to definitively evaluate the role of adiponectin and Lp(a) in cancer mortality among obese and non-obese individuals; it is possible that these associations are easier to detect in lean individuals.
The associations between baseline biomarkers and risk of cancer mortality also varied by race. IL-6 was associated with an increased risk of cancer mortality among Blacks with normal BMI and