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Title: Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention

Abstract

Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. In this paper, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation onmore » tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.« less

Authors:
 [1];  [2];  [2];  [3];  [3]; ORCiD logo [2];  [3];  [3]; ORCiD logo [3];  [4];  [1];  [1]; ORCiD logo [2]
  1. Rutgers Univ., New Brunswick, NJ (United States)
  2. Univ. of California, San Francisco, CA (United States)
  3. New York Univ. (NYU), NY (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Aeronautics and Space Administration (NASA); National Institutes of Health (NIH)
OSTI Identifier:
1637308
Grant/Contract Number:  
AC02-05CH11231; NNX09AM52G; R01CA190980; R01CA19098005S1; K08-CA172722
Resource Type:
Accepted Manuscript
Journal Name:
Cancer Immunology Research
Additional Journal Information:
Journal Volume: 8; Journal Issue: 2; Journal ID: ISSN 2326-6066
Publisher:
American Association for Cancer Research (AACR)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Omene, Coral, Ma, Lin, Moore, Jade, Ouyang, Haoxu, Illa-Bochaca, Irineu, Chou, William, Patel, Manan S., Sebastiano, Christopher, Demaria, Sandra, Mao, Jian-Hua, Karagoz, Kubra, Gatza, Michael L., and Barcellos-Hoff, Mary Helen. Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention. United States: N. p., 2019. Web. https://doi.org/10.1158/2326-6066.cir-19-0253.
Omene, Coral, Ma, Lin, Moore, Jade, Ouyang, Haoxu, Illa-Bochaca, Irineu, Chou, William, Patel, Manan S., Sebastiano, Christopher, Demaria, Sandra, Mao, Jian-Hua, Karagoz, Kubra, Gatza, Michael L., & Barcellos-Hoff, Mary Helen. Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention. United States. https://doi.org/10.1158/2326-6066.cir-19-0253
Omene, Coral, Ma, Lin, Moore, Jade, Ouyang, Haoxu, Illa-Bochaca, Irineu, Chou, William, Patel, Manan S., Sebastiano, Christopher, Demaria, Sandra, Mao, Jian-Hua, Karagoz, Kubra, Gatza, Michael L., and Barcellos-Hoff, Mary Helen. Thu . "Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention". United States. https://doi.org/10.1158/2326-6066.cir-19-0253. https://www.osti.gov/servlets/purl/1637308.
@article{osti_1637308,
title = {Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention},
author = {Omene, Coral and Ma, Lin and Moore, Jade and Ouyang, Haoxu and Illa-Bochaca, Irineu and Chou, William and Patel, Manan S. and Sebastiano, Christopher and Demaria, Sandra and Mao, Jian-Hua and Karagoz, Kubra and Gatza, Michael L. and Barcellos-Hoff, Mary Helen},
abstractNote = {Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. In this paper, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.},
doi = {10.1158/2326-6066.cir-19-0253},
journal = {Cancer Immunology Research},
number = 2,
volume = 8,
place = {United States},
year = {2019},
month = {12}
}

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