Abstract 2916: Tumor wound healing in response to treatment-induced tumor cell death increases tumor metastasis
Authors: Cook Rebecca S. 
Published: August 2015

20% of all breast cancers occur in pre-menopausal women, a relatively under-investigated group of breast cancers. These studies addressed a subset of pre-menopausal breast cancers, those which are diagnosed during post-partum involution. Post-partum breast cancers (ppBCs) account for nearly 25% of all pre-menopausal breast cancers, are more frequently diagnosed at metastatic stages than other breast cancers in young women, and correlate with decreased disease-free survival, regardless of the woman's age at the time of diagnosis or the molecular breast cancer subtype. Increasing evidence shows that stromal remodeling events that occur during post-partum involution accelerate the malignant progression of breast cancers, although the mechanisms underlying this observation have remained poorly understood.

Using transgenic mouse models of spontaneous breast cancer and allografted models of mammary tumors in immune-competent mice, we investigated pro-metastatic changes that occur during post-partum involution, recapitulating the findings that post-partum involution increases mammary tumor metastasis at least 10-fold. We investigated how physiological events that occur during post-partum involution, such as epithelial cell death, influx of macrophages, and local alterations in cytokines, might accelerate the metastasis of tumors within the post-partum mammary microenvironment. We discovered that a transient wave of widespread cell death occurs not only in normal mammary epithelial cells (MECs) during post-partum involution, but also within the mammary tumor epithelium. Like MECs in the normal mammary gland, these dying tumor cells are cleared from the tumor microenvironment by efferocytosis, the process by which macrophages or other phagocytes engulf dying cells. Efferocytosis by macrophages requires the receptor tyrosine kinase MerTK, and is followed by MerTK-mediated M2 macrophage polarization and production of pro-metastatic wound healing cytokines. Pharmacological inhibition of MerTK or genetic MerTK ablation impaired efferocytosis in the post-partum tumor microenvironment, blocked M2 macrophage polarization and dampened expression of pro-metastatic wound healing cytokines (IL-4 and TGF-β1). Further, blockade of TGFβ1 (but not IL-4) downstream of efferocytosis impaired post-partum metastasis.

These data demonstrate for the first time that 1) efferocytosis occurs in the tumor microenvironment, 2.) efferocytosis promotes a pro-metastatic microenvironment, 3.) physiological induction of widespread epithelial cell death in the post-partum breast trigger the pro-metastatic stromal remodeling events of post-partum involution, and, 4.) targeted MerTK inhibition impairs efferocytosis-induced wound healing events that contribute to enhanced metastasis.

Note: This abstract was not presented at the meeting.

Citation Format: Rebecca S. Cook. Tumor wound healing in response to treatment-induced tumor cell death increases tumor metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2916. doi:10.1158/1538-7445.AM2015-2916