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    Research Grants Awarded

    Do Mast Cells Prevent Carcinogenesis?

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    Background: Mast cells participate in inflammation, matrix degradation and tissue remodeling. An inverse correlation has been established between the accumulation of mast cells and tumor aggressiveness . Our pilot data suggest that they may play a protective role in mammary gland carcinogenesis, since mutant mast cell deficient Ws/Ws rats develop tumors after exposure to the carcinogen nitroso-methyl-urea (NMU) while their wild type counterpart do not. Hypothesis: Mast cells play a protective role in the development of breast cancer by inhibiting the development of preneoplastic lesions or by inducing their regression. Specific Aims: 1) to determine whether mast cell transplantation renders the mast cell deficient Ws/Ws rats resistant to NMU-induced carcinogenesis, 2) to determine whether mast cells prevent the development of neoplasms by blocking the formation of preneoplastic lesions or by inducing their regression in wild type rats, and 3) to assess whether inhibitors of mast cell activity enhance the formation of tumors in wild type rats. Study Design: Aim 1: the mutant mast cell deficient Ws/Ws rats will be transplanted with mast cells obtained from cultures of normal bone marrow. Mast cell replenishment will be assessed by timed skin biopsies and in the mammary glands harvested at the end of the experiment; tumors will be excised from whole mounts and confirmed by histological analysis. Aim 2: a time course of the progression/regression of pre-neoplastic lesions will be assessed in congenic wild-type and Ws/Ws mammary glands after NMU exposure. The presence, localization and type of mast cells will be determined. Aim 3: blockers of mast cell activation will be administered to assess the appearance of pre-neoplastic and neoplastic lesions in the mammary glands of wild-type animals treated with NMU. The mast cell subtype (RMCP-I or II) and degree of activation will be assessed by immunohistochemistry and image analysis. Potential outcomes and benefits: We expect to gain a better understanding of how to inhibit tumor initiation. In turn, data collected using this novel concept in carcinogenesis will help in devising, first, less aggressive therapeutic approaches in breast cancer by affecting the contribution of mast cells, and second, more reliable diagnostic cues by uncovering mast cell markers expressed during regression of neoplastic lesions.

    Lay Abstract:
    Background: Mast cells have an important role in allergic reactions and inflammation. These cells can secrete powerful chemicals: histamine that causes blood vessels’ leakiness and promotes the growth of blood vessels (angiogenesis), cytokines that cause inflammation and enzymes that degrade proteins. The great number and variety of these powerful molecules have implicated mast cells in tumor growth and metastases. Our preliminary data suggest that they may play a protective role in mammary gland carcinogenesis, since mast cell deficient Ws/Ws rats develop mammary cancer after exposure to the carcinogen nitroso-methyl-urea (NMU) while their wild-type counterparts do not. Hypothesis: Mast cells play a protective role in the development of breast cancer by inhibiting the development of preneoplastic lesions or by inducing their regression. The aims of the proposed work are: 1) to determine whether mast cell transplantation renders the mast cell deficient Ws/Ws rats resistant to NMU-induced carcinogenesis, 2) to determine whether mast cells prevent the development of palpable tumors by blocking the formation of preneoplastic lesions or by inducing their regression by comparing the evolution of preneoplastic lesions in wild type and Ws/Ws rats, and 3) to assess whether inhibitors of mast cell activity enhance the formation of tumors in wild type rats. Design: Aim 1: to compare the tumor incidence (carcinomas) between intact Ws/Ws and Ws/Ws rats transplanted with mast cells, both treated with NMU. Aim 2: To determine the time course of development, progression and regression of pre- and neoplastic lesions in the mammary glands of wild type (containing mast cells) and mast cell deficient Ws/Ws rats treated with NMU (morphometry, histology and histochemistry). Aim 3) Comparison of the time-course of development, progression and regression of pre- and neoplastic lesions in normal, wild type animals treated with inhibitors of mast cell action (same methodology as in Aim 2). Potential outcomes and benefits: This research has the potential to clarify the role of mast cells in the neoplastic process. Once the protective role of mast cells is demonstrated, their presence in biopsies may be used as a prognostic tool. In addition, this finding will open a novel rationale for intervention aimed at prevention and induced regression of neoplastic lesions.