Wounds Inhibit Tumor Growth In Vivo

Abstract

Objective: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.

Summary of background data: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.

Methods: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.

Results: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.

Conclusion: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

FIGURE 1.

Tumor ulceration or wounding slows tumor growth. (A) Schematic showing natural progression of tumor (brown) with ulceration (red) in our in vivo xenograft tumor model. (B) Representative graph of tumor growth curve with point of ulceration noted by arrow. Blue line indicates slope of tumor growth before ulceration. Red line indicates slope of tumor growth after ulceration. (C) Bar graph representing tumor growth curve slopes before and after ulceration (*P < 0.05, n = 5). (D) Schematic showing experimental model (brown=tumor; red=wound). (E) Tumor growth curve of tumors without or without full thickness excisional wounds directly above tumor (*P < 0.05, n = 10).

FIGURE 2.

Adjacent wounds inhibit tumor growth. (A) Schematic of tumor and wound competition model showing 1. Tumor only (blue), 2. Tumor wound (red), 3. Tumor 2 wounds (green), 4. Tumor sequential wounds (purple), and 5. Tumor distant wound (orange). (B) Tumor growth curve of 1. Tumor only (blue), 2. Tumor wound (red), 3. Tumor 2 wounds (green), 4. Tumor sequential wounds (purple), and 5. Tumor distant wound (orange) (n = 10).

FIGURE 3.

Ischemic flap inhibits tumor growth. (A) Schematic showing experimental model in which a cranial pedicled ischemic flap is placed caudal to a xenograft tumor. (B) Tumor growth curve of tumors with or without ischemic flaps (*P < 0.05, n = 10).

FIGURE 4.

Wounds outcompete tumors for circulating cells. (A) Schematic of parabiosis model. Following establishment of crosscirculation, wounds and tumors are created on nongreen mouse (lower left panel). (B) Fluorescence image of peripheral blood taken from NSG parabiont at 2 weeks confirming cross circulation. (C) Fluorescence-activated cell sorting (FACS) analysis plots of tumor and wound showing GFP⁺ cells (left) and bar graph (right; *P < 0.05, n = 5). (D) FACS analysis plots of tumor and wound showing GFP⁺ Lin^- cells (left) and bar graph (right; *P < 0.05, n = 5). (E) FACS analysis of daughter plots from (D) of tumor and wound showing GFP⁺ Lin^- c-Kit⁺ cells (left) and bar graph (right; *P < 0.05, n = 5). (F) FACS analysis of daughter plots from (D) of tumor and wound showing GFP⁺ Lin^- VEGFR2⁺ cells (left) and bar graph (right; *P < 0.05, n = 5).