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Purpose: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy., Experimental Design: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model., Results: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model., Conclusions: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. ©2016 AACR., (©2016 American Association for Cancer Research.)

Cancer stem-like cells (CSCs) and tumor-initiating cells (TICs) are a small population of cancer cells that share three properties: tumor initiating ability, self-renewal, and differentiation. These properties suggest that CSCs/TICs are essential for tumor maintenance, recurrence, and distant metastasis. Here, we show that cytotoxic T lymphocytes (CTLs) specific for the tumor-associated antigen CEP55 can efficiently recognize colon CSCs/TICs both in vitro and in vivo. Using Hoechst 33342 dye staining, we isolated CSCs/TICs as side population (SP) cells from colon cancer cell lines SW480, HT29, and HCT15. The SP cells expressed high levels of the stem cell markers SOX2, POU5F1, LGR5, and ALDH1A1 and showed resistance to chemotherapeutic agents such as irinotecan or etoposide.To evaluate the susceptibility of SP cells to CTLs, we used CTL clone 41, which is specific for the CEP55-derived antigenic peptide Cep55/c10orf3_193 (10) (VYVKGLLAKI). The SP cells expressed HLA class I and CEP55 at the same level as the main population cells. The SP cells were susceptible to CTL clone 41 at the same level as main population cells. Furthermore, adoptive transfer of CTL clone 41 inhibited tumor growth of SW480 SP cells in vivo. These observations suggest that Cep55/c10orf3_193(10) peptide-based cancer vaccine therapy or adoptive cell transfer of the CTL clone is a possible approach for targeting chemotherapy-resistant colon CSCs/TICs., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We established a cancer cachexia model in BALB/c mice bearing Colon 26 and examined antitumor and anticachectic activity of UFT. The mice bearing Colon 26 showed a progressive loss of body weight, loss of lipid, and hypalbuminosis associated with the change of tumor size and these symptoms were improved by removal of cancer. In this model UFT extended life span significantly at 15mg/kg/day though showed a little growth inhibitory activity. UFT showed a significant tumor growth inhibitory activity and extended life span at 20mg/kg/day and could reverse all biological parameters mentioned above. Since the intratumor and plasma contents of IL-6 were significantly lowered in the UFT administered group, it is estimated that the anticachectic activity of UFT originates from reduction of interleukin-6 in tumor.

Phase II study of a new 5-fluorouracil derivative, 5'-deoxy-5-fluorouridine (5'-DFUR), was performed with oral administration. Forty-nine patients with advanced cancer of the digestive organs, lung and breast were entered, and 8 institutions in Hokkaido were involved. 5'-DFUR was administered three or four times a day at a daily dosage of 600 to 1200 mg. Partial response was observed in three gastric cancer cases and two breast cancer cases out of 39 evaluable cases, and minor response was observed in one colorectal cancer case. Overall response rate was 12.8%, 15.8% in gastric cancer and 66.7% in breast cancer. Side effects were observed in 15 cases out of 45 (33.3%), which mainly consisted of gastro-intestinal disturbances such as diarrhea.