Abstract
Increased growth of residual tumors in the proximity of acute surgical wounds has been reported; however, the mechanisms of wound-promoted tumor growth remain unknown. Here, we used a syngeneic, orthotopic mouse model of breast cancer to study mechanisms of wound-promoted tumor growth. Our results demonstrate that exposure of metastatic mouse breast cancer cells (4T1) to SDF-1α, which is increased in wound fluid, results in increased tumor growth. Both, wounding and exposure of 4T1 cells to SDF-1α not only increased tumor growth, but also tumor cell proliferation rate and stromal collagen deposition. Conversely, systemic inhibition of SDF-1α signaling with the small molecule AMD 3100 abolished the effect of wounding, and decreased cell proliferation, collagen deposition, and neoangiogenesis to the levels observed in control animals. Furthermore, using different mouse strains we could demonstrate that the effect of wounding on tumor growth and SDF-1α levels is host dependent and varies between mouse strains. Our results show that wound-promoted tumor growth is mediated by elevated SDF-1α levels and indicate that the effect of acute wounds on tumor growth depends on the predetermined wound response of the host background and its predetermined wound response.
Highlights
Breast cancer is one of the most frequent malignant tumors observed in American women with a lifetime risk of 12% [1]
SDF-1a Levels are Increased in Wound Fluid We have previously demonstrated that wounding increases tumor growth in BALB/c wild type mice, but not in BALB/c nu/ nu mice [4]
SDF-1a levels were,1.5-fold higher in wound fluid derived from wildtype mice than in wound fluid derived from BALB/c nu/nu mice (Fig. 1B, insert) or plasma, confirming the results obtained by cytokine microarray (Fig. 1A)
Summary
Breast cancer is one of the most frequent malignant tumors observed in American women with a lifetime risk of 12% [1]. Of concern to surgeons is the potential growth stimulating effect that the host healing response, which follows the surgical removal of a primary tumor, may have on residual cancer cells left in nearby tissues and on the presence of micrometastases. In an orthotopic syngeneic mouse model of breast cancer wounds promote growth of nearby tumors [4]. Today surgical resection is the most frequently performed procedure in breast cancer treatment, and understanding the mechanisms underlying wound-promoted tumor growth is of particular importance for preventing possible adverse effects of surgery such as local recurrence. BALB/c6FVB/n animals exhibited increased tumor growth in response to wounding, this did not reach significance. As previously described [4], wounding did not increase tumor growth in BALB/ c nu/nu (Fig. 4B)
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