Systemic inflammation can promote tumor growth and counteract conventional therapies against cancer

BRUZZO, JUAN; CHIARELLA, PAULA; LANDONI VERóNICA; MEISS, ROBERTO P.; VANZULLI, SILVIA; MAGLIOCO, ANDREA; RUGGIERO, RAúL A.

Dublin

Congreso; Symposium:The role of inflammation during carcinogenesis; 2012

Although the link between cancer and local inflammation has firmly been established, the relationship between cancer and systemic inflammation (SI) has been poorly studied. Herein, we demonstrated that the growth of the murine immunogenic fibrosarcoma MC-C, was accompanied by manifestations of SI, as demonstrated by, an increase in both the number of circulating polymorphonuclear neutrophils (PMN) and the serum concentration of the proinflammatory cytokines IL-1â, IL-6, TNF-á and IFN-ã and the acute phase proteins C reactive (CRP) and serum A amyloid (SAA). Two temporally separate peaks of SI were detected during tumor development. The first was displayed during the first week after tumor inoculation. The second peak began around day 14 and its intensity was proportional to tumor size. In mice bearing a large MC-C tumor, a high number of circulating PMN and myeloid derived suppressors cells (MDSC) were evident. Most of these cells exhibited activation evidenced by an increased reactive oxygen species generation. Manifestations of SI seem to enhance tumor growth on the basis that systemic and periodic treatment with an anti-inflammatory agent -indomethacin- retarded subcutaneous tumor growth and reciprocally, systemic treatment with a pro-inflammatory agent -thioglycolate-, at the time when systemic inflammation generated by the tumor was negligible, enhanced tumor growth. At least in part, the enhancement of tumor growth by SI may be associated with an alteration of the anti-tumor immune response. In effect, treatment with a single dose of the anti-inflammatory indomethecin can restore, at least in part, the anti-tumor immune response when inoculated in tumor-bearing mice during the phase of “immunological eclipse” (primary tumor volume > 500 mm3). On the other hand, treatment with the pro-inflammatory thioglycolate impaired the expression of both sinecomitant and concomitant anti-tumor immune reaction when inoculated in pre-immunized mice as well as in tumor-bearing mice displaying concomitant immunity against secondary tumor challenges (primary tumor volume < 500 mm3). On the other hand, the attenuation of the manifestations of SI improve the anti-tumor effects obtained with surgery, immunotherapy and radiotherapy. If a systemic inflammatory condition were a hallmark of many advanced cancers, a more accurate knowledge of the underlying mechanisms by which systemic inflammation promotes tumor growth will help to design new strategies to complement and to improve the current therapies against cancer.