Wound-induced tumor progression - A probable role in recurrence after tumor resection

Objective: To determine the effect of several wound factors on melanoma growth in a mouse model. Design: Cohort analytic study. Setting: Animal research facility of Roger Williams Medical Center, Providence, RI. Study Group: Seventeen groups of 5 C57BL/6 mice each. Interventions: A surgical wound was created in 1 hind limb, after which different concentrations of B16F10 melanoma cells were injected in adjacent subcutaneous tissue. The nonwounded hind limb in the same mouse served as a control. In this fashion, a critical tumor cell dose was determined that showed tumor growth in the wounded but not the control hind limb. Tumor growth in control hind limbs then was compared with that in the "artificially wounded" hind limbs, which were co-injected with mouse wound fluid or growth factors. Early (day 1) and late (day 10) wound fluids and tumor growth factor beta (TGF-beta), basic fibroblast growth factor (bFGF), both combined, and interleukin 6 (IL-6) were used. Main Outcome Measure: Wound factors increase tumor growth, indicating potentiation of tumor recurrence at a surgical wound. Results: The critical tumor cell dose was 103 cells. All growth factors and both wound fluids showed increased tumor growth over time except IL-6. Hind limbs injected with early wound fluid showed increased tumor growth over time when compared with those injected with late wound fluid (P<.001), TGF-beta (P<.001), bFGF (P<.001), and IL-6 (P<.001). Combined TGF-beta and bFGF coinjection resulted in increased tumor growth compared with TGF-beta (P<.001) and bFGF (P<.001), but did not differ significantly from early wound fluid (P<.07). Conclusions: The healing wound and its mediators in wound fluid or purified growth factors significantly enhanced tumor growth. Combining TGF-beta and bFGF increased tumor growth to a level closer to wound fluid. The inflammatory response provoked by wound healing mediators may be an important mechanism in tumor growth after ablative surgery.