Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment Research

Background:

• Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME).
• CAFs play a significant role in mediating therapeutic resistance in various cancers.
• Understanding CAF-mediated resistance mechanisms is crucial for improving cancer treatment efficacy.

Purpose of the Study:

• To investigate the role of CAFs in the radiosensitivity of breast cancer cells.
• To elucidate the molecular mechanisms by which CAFs influence breast cancer response to radiation therapy.

Main Methods:

• Isolation of CAFs and culture of breast cancer cells using conditioned medium.
• Assessment of radiation-induced DNA damage via immunofluorescence and Western blotting.
• Analysis of cytokine secretion using cytokine arrays and ELISA.
• Evaluation of radiosensitivity through in vitro clonogenic assays and in vivo xenograft models.
• Immunohistochemical detection of hepatocyte growth factor (HGF) and c-Met expression.

Main Results:

• CAFs secrete HGF, activating the c-Met pathway in breast cancer cells, promoting epithelial-to-mesenchymal transition, growth, and radioresistance.
• Radiation enhances HGF secretion by CAFs and c-Met expression in cancer cells, activating the HGF/c-Met pathway.
• Radiation-induced TNFα secretion by cancer cells stimulates CAF proliferation and HGF secretion.
• High HGF and c-Met expression correlated with poorer recurrence-free survival in patients receiving radiation therapy.

Conclusions:

• HGF and TNFα mediate critical crosstalk between breast cancer cells and CAFs within the TME.
• The HGF/c-Met signaling pathway represents a potential therapeutic target for enhancing breast cancer radiosensitivity.