Prostaglandin E2 Release from Breast Tumor Induces Premetastatic Niche Formation and Metastasis in the Lung
Abstract
In 2019 alone, over 268,600 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 lines of compelling preliminary data including (1) preclinical evidence of increased metastasis in biopsied mice compared to unbiopsied ones, (2) clinical observation of the appearance of BC cells with invasive morphology adjacent to post-biopsy site exhibiting chronic inflammation with accumulation of mesenchymal stem cells (MSCs), and (3) epidemiologic evidence (National Cancer Database [NCDB]; n=210,533) of a steep and continuous increase in mortality risk 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 the biology underlying how BC progression can occur over just 35 days to a level that negatively impacts survival. Our preclinical mouse models have indicated that needle biopsy of tumors leaves a uniquely unhealed chronic wound. Similarly, microscopic examination of the biopsy-wound site in human BC cases revealed significant infiltration of mesenchymal stem cells, which are potent producers of the inflammatory mediator, Prostaglandin E2 (PGE2). Accordingly, high levels of PGE2 were present in biopsied tumors and blood, suggesting the constant release of PGE2 into the blood stream following biopsy. We found that circulating PGE2 enhances dissemination of BC cells to the lung in mice through the formation of pre-metastatic niche, the entry site for BC cells to organs from the blood stream. In fact, compelling pilot data suggested that oral administration of over-the-counter anti-inflammatory drugs (ibuprofen) to block the biosynthesis of PGE2 effectively inhibited biopsy-associated metastasis in mice. Based on these preliminary observations, we aim to elucidate the mechanism behind biopsy-driven metastasis (Aim 1). Following this, we will study the effect of common PGE2 signaling inhibitors on blocking the biopsy-induced pre-metastatic niche formation that leads to organ metastasis (Aim 2). Despite the growing scope of surgical delay, the survival benefit of basic measures (i.e., timely surgery) has 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 2019 at risk of surgical delay-associated mortality, disproportionately affecting women from racial/ethnic minorities and lower socioeconomic status. Reflecting the knowledge gap surrounding the apparent mortality risk posed by surgical 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, the establishment of guidelines for allowable time to surgery after diagnosis is severely and urgently needed to avoid survival disadvantages among breast cancer patients whose first treatment is surgery. A
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010555
Entities
People
- Hallgeir Rui
Organizations
- Medical College of Wisconsin
- United States Army