Title:
Approaches for immunopathology of cancer stem cells: from basics to therapeutic application

Toshihiko Torigoe, MD, PhD.
Associate Professor,
Department of Pathology,
Sapporo Medical University School of Medicine

Abstract:
Cancer stem-like cells (CSCs) are defined as the small population of cancer cells that have stem cell-like phenotypes and high capacity for tumor initiation. These cells may have a huge impact in the field of cancer therapy since they are extremely resistant to standard chemotherapy and thus are likely to be responsible for disease recurrence. We have analyzed the immunopathological properties of CSCs of human solid cancer cells and identified several genes that were characteristic to CSCs. Remarkably, some of them were expressed exclusively in testicles among normal adult organs and involved in the spermatogenesis and function of spermatozoa. siRNA-mediated knockdown of these genes caused decreased sphere-forming capacity and tumor-initiating capacity, therefore indicating that they might be associated with the maintenance of stem-like phenotype of CSCs. Furthermore, it was indicated that expression of the CSC-specific genes might be regulated by epigenetic mechanisms such as histone modification and DNA methylation. Our data suggest that spermatogenesis-associated genes are aberrantly expressed in CSCs and function as key molecules to stress tolerance and tumor initiation. In the field of tumor immunology, the CSC-specific gene products might serve as ideal targets for cancer immunotherapy. We show evidence that CSC-specific cytotoxic T-cells are induced from peripheral blood of cancer patients, and propose an immunotherapeutic strategy targeting to CSCs.

References:
1. Torigoe T, et al. Constitutive expression and activation of stress response genes in cancer stem-like cells/tumour initiating cells: potent targets for cancer stem cell therapy. Int J Hyperthermia 29: 436-441, 2013.

2. Yasuda K, Torigoe T, et al. Ovarian cancer stem cells are enriched in side population and aldehyde dehydrogenase bright overlapping population. PLoS One 8: e68187, 2013.

3. Yamada R, Takahashi A, Torigoe T, et al. Preferential expression of cancer/testis genes in cancer stem-like cells: proposal of a novel sub-category, cancer/testis/stem gene. Tissue Antigens 81: 428-434, 2013.

4. Nishida S, Hirohashi Y, Torigoe T, et al. Prostate cancer stem-like cells/cancer-initiating cells have an autocrine system of hepatocyte growth factor. Cancer Sci 104: 431-436, 2013.

5. Kuroda T, Hirohashi Y, Torigoe T, et al. ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis. PLoS One 8: e65158, 2013.

6. Nishizawa S, Hirohashi Y, Torigoe T, et al. Heat shock protein DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells. Cancer Res 72: 2844-2854 , 2012.

7. Hirohashi Y, Torigoe T, et al. Immune response against tumor antigens expressed on human cancer stem-like cells/tumor-initiating cells. Immunotherapy 2: 201-211, 2010.