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      Hyaluronan, Inflammation, and Breast Cancer Progression

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          Abstract

          Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory “cancerized” or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression.

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          Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

          Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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            CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

            Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.
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              Hyaluronan as an immune regulator in human diseases.

              Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/205190
                URI : http://frontiersin.org/people/u/153645
                URI : http://frontiersin.org/people/u/234157
                URI : http://frontiersin.org/people/u/149755
                URI : http://frontiersin.org/people/u/213675
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                08 June 2015
                2015
                : 6
                : 236
                Affiliations
                [1] 1Department of Laboratory Medicine and Pathology, Masonic Comprehensive Cancer Center, University of Minnesota , Minneapolis, MN, USA
                [2] 2Biomatrix Research Center, Department of Chemical and Biomolecular Engineering, New York University Polytechnic School of Engineering , New York, NY, USA
                [3] 3Department of Oncology, London Health Science Center, Schulich School of Medicine, Western University , London, ON, Canada
                [4] 4Department of Biochemistry and Surgery, London Health Science Center, Schulich School of Medicine, Western University , London, ON, Canada
                Author notes

                Edited by: David Naor, Hebrew University of Jerusalem, Israel

                Reviewed by: Sumit Ghosh, North Dakota State University, USA; Jason C. Mills, Washington University School of Medicine, USA

                *Correspondence: James B. McCarthy, University of Minnesota, 5-144 Molecular Cellular Biology Building, 609 MMC 420, Delaware Street SE, Minneapolis, MN 55455, USA, mccar001@ 123456umn.edu

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00236
                4459097
                26106384
                ec90b656-8d6c-4a8f-ae05-5485700a6462
                Copyright © 2015 Schwertfeger, Cowman, Telmer, Turley and McCarthy.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 February 2015
                : 01 May 2015
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 130, Pages: 12, Words: 10747
                Funding
                Funded by: NIH
                Award ID: R01 CA132827
                Funded by: Movember Prostate Cancer Society
                Funded by: The Endre A. Balazs Foundation
                Funded by: Chairman’s Fund Professor in Cancer Research
                Categories
                Immunology
                Review

                Immunology
                hyaluronan,breast cancer,inflammation,tumor microenvironment,rhamm/hmmr,cd44,macrophage
                Immunology
                hyaluronan, breast cancer, inflammation, tumor microenvironment, rhamm/hmmr, cd44, macrophage

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