Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy

Cancer Res. 2015 Sep 1;75(17):3479-91. doi: 10.1158/0008-5472.CAN-14-3587. Epub 2015 Aug 12.

Abstract

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Chemokine CXCL12 / biosynthesis
  • Chemokine CXCL12 / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Mice
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / genetics*
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / biosynthesis*
  • Receptors, CXCR4 / genetics
  • Signal Transduction / drug effects
  • Tamoxifen / administration & dosage
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Vascular Endothelial Growth Factor A
  • Tamoxifen