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      Mammary tumor growth and metastasis are reduced in c‐Kit mutant Sash mice

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          Abstract

          Besides its well‐known function in allergic response, mast cell, one of the key immune cells present in tumor microenvironment, plays important roles in cancer progression. However, the functional role of mast cells in breast cancer development and metastasis is not well understood. To test the involvement of mast cells in breast cancer, we examined the effects of loss of mast cells on mammary tumor development by crossing the well‐known mast cell deficient mouse strain sash (Kit W‐sh/W‐sh) with the mammary tumor transgenic mouse strain MMTV‐Polyoma Middle T antigen (Py MT). Although mammary tumor onset was not affected in the absence of mast cells, mammary growth and metastasis were reduced in Py MT/Kit W‐sh/W‐sh mice compared with Py MT/wild‐type mice ( WT). Histological and immunofluorescent analyses showed that tumors from Py MT/Kit W‐sh/W‐sh mice showed largely differentiated morphology with reduced angiogenesis compared with MMTV‐Py MT/ WT mice. Our results suggest that mast cells may promote breast cancer growth and metastasis. Agents that can block mast cells growth are potential new therapies to treat metastatic breast cancer.

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          Macrophages regulate the angiogenic switch in a mouse model of breast cancer.

          The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.
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            MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.

            The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
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              Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis.

              Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.
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                Author and article information

                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                19 March 2016
                June 2016
                : 5
                : 6 ( doiID: 10.1002/cam4.2016.5.issue-6 )
                : 1292-1297
                Affiliations
                [ 1 ] Key Laboratory of Laboratory Medicine Ministry of Education School of Laboratory Medicine and Life ScienceWenzhou Medical University Wenzhou 325035China
                [ 2 ] Department of PathologyUniversity of Colorado Anschutz Medical Campus Aurora Colorado 80045
                Author notes
                [*] [* ] Correspondence

                Haihua Gu, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Chashan Higher Education Park, Wenzhou, 325035 Zhejiang, China. Tel: 86‐0577‐86691317; Fax: 86‐0577‐86689771;E‐mail: haihuagu@ 123456gmail.com

                Article
                CAM4696
                10.1002/cam4.696
                4924387
                26992445
                d36a265f-35f0-48a1-9443-9b026885ec8e
                © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 December 2015
                : 21 January 2016
                : 14 February 2016
                Page count
                Pages: 6
                Funding
                Funded by: Natural Science Foundation of Zhejiang Province, China
                Award ID: LQ13H080002
                Funded by: National Natural Science Foundation of China
                Award ID: 81372826
                Award ID: 81400125
                Categories
                Short Report
                Cancer Biology
                Short Report
                Custom metadata
                2.0
                cam4696
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:28.06.2016

                Oncology & Radiotherapy
                breast cancer,mast cells,metastasis,mouse models,tumor growth
                Oncology & Radiotherapy
                breast cancer, mast cells, metastasis, mouse models, tumor growth

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