Surgical wounding enhances pro‐tumor macrophage responses and accelerates tumor growth and lung metastasis in a triple negative breast cancer mouse model

• Published in: Physiological reports Vol. 10; no. 21; pp. e15497 - n/a
• Main Authors: McDonald, Sierra J., VanderVeen, Brandon N., Bullard, Brooke M., Cardaci, Thomas D., Madero, Sarah S., Chatzistamou, Ioulia, Fan, Daping, Murphy, E. Angela
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2022; John Wiley and Sons Inc; Wiley
• Subjects: Animal models; Animals; Apoptosis; Breast cancer; Cancer therapies; Cell Line, Tumor; Disease Models, Animal; Female; Flow cytometry; Gene expression; Histopathology; Humans; Immunofluorescence; inflammation; Laboratory animals; Lung cancer; Lung Neoplasms; Lungs; Macrophages; Macrophages - metabolism; Metastases; Metastasis; Mice; Original; Skin; Surgery; surgical wounding; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; Wounding; United States > US; South Carolina; breast cancer; macrophages; surgical wounding; inflammation; metastasis
• ISSN: 2051-817X
• DOI: 10.14814/phy2.15497

Approximately one‐third of all breast cancer mortality results from metastatic recurrence after initial success of surgery and/or therapy. Although primary tumor removal is widely accepted as beneficial, it has long been suspected that surgery itself contributes to accelerated metastatic recurrence. We investigated surgical wounding's impact on tumor progression and lung metastasis in a murine model of triple negative breast cancer (TNBC). Ten‐week‐old female mice were inoculated with 4 T1 cells (week 0) and were either subjected to a 2 cm long cutaneous contralateral incision (wounded) or control (non‐wounded) on week 2 and monitored for 3 weeks (week 5). Mice with surgical wounding displayed significantly accelerated tumor growth observable as early as 1‐week post wounding. This was confirmed by increased tumor volume and tumor weight, post‐mortem. Further, surgical wounding increased metastasis to the lungs, as detected by IVIS imaging, in vivo and ex vivo (week 5). As expected then, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. Flow cytometry revealed that primary tumors from wounded mice exhibited increased tumor associated macrophages and specifically M2‐like macrophages, which are important in promoting tumor development, maintenance, and metastasis. Immunofluorescence staining and gene expression data further confirms an increase in macrophages in both the primary tumor and the lungs of wounded mice. Our data suggests that surgical wounding accelerates tumor progression and lung metastasis in a mouse model of TNBC, which is likely mediated, at least in part by an increase in macrophages. Our study documents that mice with surgical wounding, at a distant site and without tumor resection, displayed acceleration of primary tumor growth as well as significantly enhanced lung metastasis in a triple negative breast cancer model. Further, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. These responses were associated with an increase in macrophages in both the primary tumor and in the lungs of wounded mice.