Journal
ENDOCRINOLOGY
Volume 160, Issue 8, Pages 1895-1906Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2019-00362
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Funding
- Strategic Research Center in Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Practical Research for Innovative Cancer Control [JP18ck0106194]
- Project for Cancer Research and Therapeutic Evolution [P-CREATE] from the Japan Agency for Medical Research and Development [JP18cm0106144]
- Japan Society for the Promotion of Science, Japan [16K09809, 16K15496, 17H04205, 17K16170]
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17K16170, 16K15496] Funding Source: KAKEN
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Low-grade and early-stage endometrial cancer usually has a favorable prognosis, whereas recurrent or metastatic disease is often difficult to cure. Thus, the molecular mechanisms underlying advanced pathophysiology remain to be elucidated. From the perspective of the origin of advanced endometrial cancer, the characterization of cancer stem-like cells (CSCs) will be the first step toward the development of clinical management. We established long-term culturable patient-derived cancer cells (PDCs) from patient endometrial tumors by spheroid cell culture, which is favorable for the enrichment of CSCs. PDC-derived xenograft tumors were generated in immunodeficient NOD/Shi-scid, IL-2R gamma KO Jic mice. Morphologically, PDCs derived from three distinct patient samples and their xenograft tumors recapitulated the corresponding original patient tumors. Of note, CSC-related genes including ALDH1A1 were upregulated in all of these PDCs, and the therapeutic potentiality of aldehyde dehydrogenase inhibitors was demonstrated. In addition, these PDCs and their patient-derived xenograft (PDX) models exhibited distinct characteristics on the basis of their hormone responsiveness and metastatic features. Interestingly, genes associated with inflammation and tumor immunity were upregulated by 17 beta-estradiol in PDC lines with high estrogen receptor expression and were also overexpressed in secondary PDCs obtained from metastatic tumor models. These results suggest that PDC and PDX models from endometrial cancer specimens would be useful to elucidate CSC traits and to develop alternative diagnostic and therapeutic options for advanced disease.
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