A Stromal CCL2/CCR2 Signaling Axis Regulates Chemotherapeutic Response in a Mouse Model of Breast Cancer

Nakasone, Elizabeth (March 2012) A Stromal CCL2/CCR2 Signaling Axis Regulates Chemotherapeutic Response in a Mouse Model of Breast Cancer. PhD thesis, Cold Spring Harbor Laboratory.

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Abstract

The complex array of extracellular matrix molecules, immune cells, blood and lymph systems, and fibroblasts that comprises the tumor’s stromal compartment influences tumor initiation, progression, metastasis, and therapeutic response. In breast cancer, myeloid cells make up a prominent proportion of the tumor stroma, and enhanced infiltration of these immune cells into tumors is associated with advanced disease and decreased relapse-free survival. Furthermore, highlevel infiltration of myeloid cells into tumors following radiation therapy and chemotherapy is frequently observed in pre-clinical models. We therefore sought to determine the significance of myeloid cell recruitment following chemotherapy treatment and their role in therapeutic resistance. Using intravital imaging of tumors in live mice, we observed that the tumors of the polyoma middle T antigen (PyMT) mouse model of luminal breast cancer show a stage-dependent sensitivity to treatment with doxorubicin. Doxorubicin treatment induces necrosis in drug-sensitive lesions, which consequently results in the recruitment of CCR2+Gr1+7/4+CD11b+ immature myeloid cells with monocytic morphology. Inhibiting recruitment of these cells via orthotopic transplantation of Ccr2+/+ cancer cells from PyMT mice into Ccr2-/- mice delays tumor relapse indicating a role for these monocytic cells in chemoresistance. Changes in tumor vasculature and tumor grade accompany the delay in host relapse, indicating that CCR2 signaling may also have important effects on tumor angiogenesis and cancer cell differentiation and proliferation. This is further confirmed by the fact that transgenic PyMT;Ccr2-/- mice respond better to doxorubicin from the outset. The data herein presented show that antagonism of CCR2 signaling in combination with cytotoxic chemotherapy treatment may be a potentially powerful therapeutic strategy for the treatment of breast cancer.

Item Type: Thesis (PhD)
Subjects: Investigative techniques and equipment > biomarker
diseases & disorders > cancer > cancer types > breast cancer
diseases & disorders > cancer > drugs and therapies > chemotherapy
Investigative techniques and equipment > microscopy > immunoflourescence microscopy
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Watson School > Theses
Depositing User: Matt Covey
Date: 31 March 2012
Date Deposited: 29 Nov 2012 20:27
Last Modified: 21 Sep 2016 18:39
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26269

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