A CXCL1 paracrine network links cancer chemoresistance and metastasis. Academic Article uri icon

Overview

abstract

  • Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.

publication date

  • July 6, 2012

Research

keywords

  • Breast Neoplasms
  • Carcinoma
  • Chemokine CXCL1
  • Drug Resistance, Neoplasm
  • Neoplasm Metastasis
  • Paracrine Communication

Identity

PubMed Central ID

  • PMC3528019

Scopus Document Identifier

  • 84863625224

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.04.042

PubMed ID

  • 22770218

Additional Document Info

volume

  • 150

issue

  • 1