Accession Number:

ADA574527

Title:

Priming the Tumor Immune Microenvironment Improves Immune Surveillance of Cancer Stem Cells and Prevents Cancer Recurrence

Descriptive Note:

Annual rept. 15 Sep 2011-14 Sep 2012

Corporate Author:

SCRIPPS RESEARCH INST LA JOLLA CA

Personal Author(s):

Report Date:

2012-10-01

Pagination or Media Count:

11.0

Abstract:

The cancer stem cell CSC hypothesis has gained significant recognition as a descriptor of tumorigenesis. Additionally, tumor-associated macrophages TAMs are known to promote growth and metastasis of breast cancer. However, it is not known whether TAMs mediate tumorigenesis through regulation of breast CSCs. Here, we report that TAMs promote CSC-like phenotypes in murine breast cancer cells by upregulating their expression of Sox-2. These CSC-like phenotypes were characterized by increased Sox-2, Oct-4, Nanog, AbcG2 and Sca-1 gene expression, in addition to increased drug efflux capacity, resistance to chemotherapy and increased tumorigenicity in vivo. Downregulation of Sox-2 in tumor cells by siRNA blocked the ability of TAMs to induce these CSC-like phenotypes and inhibited tumor growth in vivo. Furthermore, we identified a novel EGFRStat3Sox-2 paracrine signaling pathway between macrophages and mouse breast cancer cells that is required for macrophage-induced upregulation of Sox-2 and CSC phenotypes in tumor cells. We showed that this crosstalk was effectively blocked by the small molecule inhibitors AG1478 or CDDO-Im against EGFR and Stat3, respectively. Therefore, our report identifies a novel role for TAMs in breast CSC regulation and establishes a rationale for targeting the EGFRStat3Sox-2 signaling pathway for cancer stem cell therapy.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE