SDF1 Promotes Organ Metastasis in Chronically Inflamed Breast Tumors
Abstract
In 2020 alone, over 279,100 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. 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 emergence of BC cells with invasive morphology adjacent to the biopsy wound, which exhibits chronic inflammation with accumulation of M2 macrophages; and 3) epidemiologic evidence (National Cancer Database; n=226,786) of a steep and continuous increase in mortality risk of 5%-6% every week starting 38 days after diagnostic biopsy in early-stage BC patients who receive surgery as first-line treatment. Over 35% of women with early-stage BC experienced surgical delay beyond 38 days in 2016. Given the steep increase in mortality risk accrued over a relatively short period, it is critical to 1) understand the biopsy underlying biopsy-associated changes that lead to BC progression occurs over just 38 days to a level that negatively impacts survival and to 2) develop strategies to prevent it. Our preliminary study showed that needle biopsy of breast tumors leaves an unhealed chronic wound in both humans and mice. Due to unresolved inflammation, the level of COX2, an enzyme for PGE2 biosynthesis, remained high in biopsied tumors, skewing infiltrating macrophages towards a M2 phenotype that produces SDF1 at the biopsied site. Hypoxia within the biopsy wound locally upregulates CXCR4, a canonical receptor for SDF1, in BC cells, thereby coordinately promoting acquisition of invasive BC cell behavior. In parallel, soluble factors released by biopsy wound induce expression of SDF1 on pulmonary vessels, allowing entry of CXCR4+ BC cells into the lung tissue. Thus, SDF1 has dual pro-metastatic functions in the primary tumor and secondary organs. Reflecting the key initiating role of COX2 in the primary tumor, compelling pilot data suggested that oral administration of over-the-counter anti-inflammatory drugs (ibuprofen) to block COX2 signaling 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 local delivery of COX2 inhibitors on biopsy-induced organ metastasis (Aim 2). Despite the growing magnitude of surgical delays for early-stage BC patients, the survival benefit of basic measures (i.e., timely surgery) has been largely overlooked. Alarmingly, the proportion of women who experience surgical delay over 38 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 from 23 days in 2004 to 32 days in 2016. This places an estimated 45,774 women diagnosed with early-stage BC in 2020 at risk of surgical delay-associated mortality, and sadly disproportionately affects racial/ethnic minorities and financially disadvantaged women. Reflecting the knowledge gap surrounding the apparent mortality risk posed by surgical delay, no standard guideline for the allowable time between diagnosis and surgery is currently 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 di
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110003
Entities
People
- Takemi Tanaka
Organizations
- United States Army
- University of Oklahoma Health Sciences Center