Bone Marrow-Derived Mesenchymal Stem Cells in Biopsy Wound Promote Breast Cancer Progression and Metastasis
Abstract
In 2008 alone, over 266,000 new breast cancer (BC) cases are expected in the U.S. While early-stage BC is the most common diagnosis, patients still face the lingering threat of disease recurrence long after successful surgical removal of the primary tumor and affected lymph nodes. Although the mechanism of early-phase disease dissemination is not fully understood, we identified “time from biopsy to surgery” as an independent prognostic factor in early-stage BC patients. Therefore, the central hypothesis of this proposal is that diagnostic biopsy promotes metastatic changes in early-stage BC. This radically new concept is underpinned by three stems of our preliminary data including: (1) preclinical evidence of increased metastasis in biopsied mice compared to unbiopsied ones, (2) clinical evidence of retention of an unhealed wound at the post-biopsy site for months accompanied by the appearance of invasive BC cells, and (3) epidemiologic evidence (National Cancer Database [NCDB]; n=210,533) of a steep and continuous increase in mortality of 5%-6% every other week starting 35 days after diagnostic biopsy in early-stage BC patients. Over 30% of women with early-stage BC experienced surgical delay beyond 35 days from 2004 to 2014 in our NCDB cohort. Given the steep increase in mortality risk accrued over a relatively short period, it is critical to understand biology underlying how BC progression can occur over just 35 days to a level that negatively impacts the survival. Our preclinical mouse models have indicated that needle biopsy of tumors leaves a uniquely unhealed chronic wound that interacts with the cancer cells through Prostaglandin E2 inflammatory pathways that promote more aggressive phenotypes and subsequently metastasis. Microscopic examination of the biopsy-wound site in human BC cases revealed significant infiltration of cytokine-producing macrophages and mesenchymal stem cells in close proximity to cancer cells undergoing epithelial to mesenchymal transition (EMT) at rates significantly higher than cancer cells distant from the residual biopsy wound. In fact, oral administration of an over-the-counter anti-inflammatory drug to block biosynthesis of Prostaglandin E2 effectively inhibited biopsy-induced metastasis in mice. Based on these preliminary observations, we aim to elucidate the mechanism behind the biopsy-driven acquisition of phenotypic traits conducive to metastasis (Aim 1). Following this, we will study the effect of common Prostaglandin E2 signaling inhibitors (such as over-the-counter NSAIDs [nonsteroidal anti-inflammatory drugs]) on blocking the biopsy-induced inflammatory cascade that leads to higher incidence of metastasis (Aim 2). Despite the scope of this issue, the survival benefit of basic measures (i.e., timely surgery) have been largely overlooked. Alarmingly, the proportion of women who experience surgical delay over 35 days is expected to rise based on our finding that the median interval between diagnostic biopsy and surgery for early-stage BC has annually increased at a rate of approximately 1 day each year, from 23 days in 2004 to 32 days in 2015. This places an estimated 37,000 women diagnosed with early-stage BC in 2018 at risk of surgical delay-associated mortality, disproportionately affecting women from racial/ethnic minorities and lower socioeconomic status. Reflecting the knowledge gap surrounding the mortality risk posed by surgery delay, currently no standard guideline for the allowable time between diagnosis and surgery is available in the U.S., although recommended timelines for other therapies (chemo, endocrine, and radiation) have been defined as established quality measures. Therefore, establishment of guidelines for allowable time to surgery after diagnosis is severely and urgently needed for the protection of survival benefit to all women whose first treatment is surgery. A concrete biologic explanation of how breast tumors rapidly undergo pro-metastati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910357
Entities
People
- Hallgeir Rui
Organizations
- Medical College of Wisconsin
- United States Army