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Morphometric analysis of immunoselection against hyperploid cancer cells.
Norma Bloy1,2,3,4, Allan Sauvat1,3,4,5, Kariman Chaba1,3,4
1Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 75006 Paris, France.
Oncotarget
|October 31, 2015
Summary
Cancer cells with increased ploidy and endoplasmic reticulum (ER) stress are hyperploid in immunodeficient mice. These cells fail to grow in immunocompetent mice and instead trigger an anticancer immune response.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Ploidy changes, often via whole genome duplication, are common in oncogenesis, affecting over 40% of solid cancers.
- Methylcholanthrene (MCA)-induced fibrosarcomas provide a model to study ploidy in cancer development.
Purpose of the Study:
- To investigate the impact of the immune environment on the ploidy status of MCA-induced fibrosarcomas.
- To explore the relationship between hyperploidy, endoplasmic reticulum (ER) stress, and tumor formation in different immune-deficient models.
- To develop and validate a novel morphometric tool for analyzing ploidy and ER stress in fixed tissues.
Main Methods:
- Induction of fibrosarcomas in immunocompetent wild type and immunodeficient Rag2-/-γc-/- mice using MCA.
- Comparative analysis of tumor ploidy, DNA content, nuclear surface, and eukaryotic initiation factor 2α (eIF2α) phosphorylation in different mouse models.
- Development of a morphometric analysis software for quantifying nuclear surface and eIF2α phosphorylation in immunohistochemically stained tissues.
Main Results:
- MCA-induced fibrosarcomas exhibit distinct ploidy statuses depending on the host's immune competence, with higher hyperploidy observed in immunodeficient settings.
- Hyperploid fibrosarcomas from immunodeficient mice show increased DNA content, larger nuclear surface, and elevated eIF2α phosphorylation, indicating ER stress.
- Transplantation of these hyperploid, ER-stressed cells into wild type mice resulted in failed proliferation and induction of an anticancer immune response.
- Conversely, these cells formed tumors in Rag2-/-γc-/- and Rag2-/- recipients, maintaining their hyperploid and ER-stressed phenotype.
Conclusions:
- The immune microenvironment significantly influences the ploidy and ER stress levels of developing fibrosarcomas.
- Hyperploid, ER-stressed cancer cells originating in an immunodeficient setting can be rejected by a competent immune system, potentially serving as a basis for immunotherapy.
- The developed morphometric tool is effective for in situ analysis of ploidy and ER stress in cancer tissues.
