Purpose: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis.
Experimental Design: 4T1 cells were injected in 20 Gy preirradiated mammary tissue to mimic postradiation relapses, or in nonirradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histologic analyses, adoptive cell transfer, genetic, and pharmacologic interventions were carried out.
Results: Tumors growing in preirradiated mammary tissue had reduced angiogenesis and were more hypoxic, invasive, and metastatic to lung and lymph nodes compared with control tumors. Increased metastasis involved the mobilization of CD11b(+)c-Kit(+)Ly6G(high)Ly6C(low)(Gr1(+)) myeloid cells through the HIF1-dependent expression of Kit ligand (KitL) by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and premetastatic lungs, to give rise to CD11b(+)c-Kit(-) cells. Pharmacologic inhibition of HIF1, silencing of KitL expression in tumor cells, and inhibition of c-Kit with an anti-c-Kit-blocking antibody or with a tyrosine kinase inhibitor prevented the mobilization of CD11b(+)c-Kit(+) cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b(+)c-Kit(+) cells and inhibiting lung metastasis after irradiation of established tumors.
Conclusions: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in preirradiated mammary tissue. Pharmacologic inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1158/1078-0432.CCR-11-3028 | DOI Listing |
Adv Sci (Weinh)
January 2025
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
Hydrogen sulfide (HS)-mediated protein S-sulfhydration has been shown to play critical roles in several diseases. Tumor-associated macrophages (TAMs) are the predominant population of immune cells present within solid tumor tissues, and they function to restrict antitumor immunity. However, no previous study has investigated the role of protein S-sulfhydration in TAM reprogramming in breast cancer (BC).
View Article and Find Full Text PDFAnn Surg Oncol
January 2025
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Background: Bilateral risk-reducing mastectomies (RRMs) have been proven to decrease the risk of breast cancer in patients at high risk owing to family history or having pathogenic genetic mutations. However, few resources with consolidated data have detailed the patient experience following surgery. This systematic review features patient-reported outcomes for patients with no breast cancer history in the year after their bilateral RRM.
View Article and Find Full Text PDFAnn Surg Oncol
January 2025
Department of Plastic and Reconstructive Surgery, The Ohio State University, Columbus, OH, USA.
Cancer Causes Control
January 2025
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York at Buffalo, 265 Farber Hall, Buffalo, NY, 14214, USA.
Purpose: Historical redlining, a 1930s-era form of residential segregation and proxy of structural racism, has been associated with breast cancer risk, stage, and survival, but research is lacking on how known present-day breast cancer risk factors are related to historical redlining. We aimed to describe the clustering of present-day neighborhood-level breast cancer risk factors with historical redlining and evaluate geographic patterning across the US.
Methods: This ecologic study included US neighborhoods (census tracts) with Home Owners' Loan Corporation (HOLC) grades, defined as having a score in the Historic Redlining Score dataset; 2019 Population Level Analysis and Community EStimates (PLACES) data; and 2014-2016 Environmental Justice Index (EJI) data.
Apoptosis
January 2025
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
Cancer-associated fibroblasts (CAFs) significantly influence tumor progression and therapeutic resistance in colorectal cancer (CRC). However, the distributions and functions of CAF subpopulations vary across the four consensus molecular subtypes (CMSs) of CRC. This study performed single-cell RNA and bulk RNA sequencing and revealed that myofibroblast-like CAFs (myCAFs), tumor-like CAFs (tCAFs), inflammatory CAFs (iCAFs), CXCL14CAFs, and MTCAFs are notably enriched in CMS4 compared with other CMSs of CRC.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!