Cancer stem-like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC.

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 ( Colon cancer is one of the most common malignancies worldwide. With recent progress in treatment, the prognosis has improved to some extent. In advanced disease, however, the prognosis remains unfavorable, because of recurrence, distant metastasis, and resistance to treatment. Thus, novel treatment modalities are needed.Cancers contain morphologically heterogeneous populations. This fact has led to the cancer stem cell theory, 1 the idea that cancers are composed of several types of cells, and that only a small population of cancer cells that can regenerate cancer tissues, much as normal tissue can be regenerated only by a small population of stemlike cells. Recently, cancer stem-like cells and tumorinitiating cells (CSCs/TICs) have been isolated from various types of malignancies, including colon cancer.2-6 In colon cancer, CSCs/TICs can reinitiate tumors that resemble mother colon cancer tissues morphologically when transplanted into immunodeficient mice.3 Furthermore, these CSCs/TICs have higher tumorigenic potential than do non-CSCs/TICs. Previous reports have shown that CSCs/TICs are resistant to a variety of treatments, including chemotherapy and radiotherapy, with varied mechanisms of resistance, including high expression of drug transporters, relative cell cycle quiescence, high levels of DNA repair machinery, and resistance to apoptosis. 7 These reports 3-6 support the hypothesis that malignant cancers comprise heterogeneous populations that organize in a hierarchical differentiation model. The CSCs/TICs are located at the top of this hierarchy, and targeting CSCs/TICs is essential to achieve efficient effects for treatment of malignant diseases. Recently, some trials targeting CSCs/TICs have been reported for hema-

Background  A population‐based prospective cohort study was undertaken to examine the predictors of functional decline in instrumental activities of daily living (I‐ADL) among non‐disabled older Japanese subjects living in a rural community during a five‐year interval from 1992 to 1997. Methods  The subjects consisted of 624 men and women aged from 65–89 years and independent in I‐ADL at baseline, who could be completely followed for five years. Independent variables were various physical factors potentially associated with higher level of functional capacity obtained from an interview survey and medical examinations at baseline. Dependent variables were functional status in I‐ADL obtained at the time of the 5‐year follow‐up. Results  Significant predictors of functional decline in I‐ADL during a 5‐year follow‐up period included: (1) older age; (2) higher blood pressure; and (3) lower maximum walking speed at baseline. Among these predictor, the maximum walking speed is likely to the strongest predictor for the decline in I‐ADL. Conclusion  The ability to walk faster in the old age is strongly associated with independence in the other I‐ADL, and walking speed should be modified by the lifestyle to strengthen muscles of the lower extremities in daily life.

The primary purposes of this study were 1) to confirm age-related deterioration of physical performance in older adults longitudinally, and 2) to predict future functional status and mortality by initial level of physical performances. The subjects were 517 older adults examined both in 1992 and 1996 in the Tokyo Metropolitan Institute of Gerontology, Longitudinal Interdisciplinary Study on Aging. The same battery consisting of muscle strength, balance, walking, and manual speed was administered to the subjects in the baseline and follow-up examinations. A significant longitudinal decline was observed in all physical performances except for grip strength. The age-related decline accelerated with aging for preferred walking velocity. Inter-subject variability in walking velocity significantly increased for 4 years period. Maximum walking velocity was a common predictor for functional status and mortality. The results suggest that physical performance measures, especially maximum walking velocity, is a valid means for physical therapy to evaluate physical functioning of community-living older persons.

Cancer stem-like cells (CSCs)/tumor-initiating cells (TICs) are a small population of cancer cells that have the properties of tumor-initiating ability, self-renewal and differentiation. These properties suggest that CSCs/TICs are essential for tumor maintenance, recurrence and distant metastasis. Thus, elimination of CSCs/TICs is essential to cure malignant diseases. However, there are several studies reporting that CSCs/TICs are more resistant to standard cancer therapies, including chemotherapy and radiotherapy, than non-CSC/TIC populations. How then, can we eliminate CSCs/TICs? Immunotherapy might be the possible answer. In recent analysis, innate immunity (natural killer cells and gammadeltaT cells) and also adaptive immunity (cytotoxic T lymphocyte-based cellular immunity and antibody-based humoral immunity) can recognize CSCs/TICs in vitro efficiently. Furthermore, CSC/TIC-specific monoclonal antibody therapies are also efficient in vivo. In this article, we describe the potency, possibilities and problems of CSC/TIC-targeting immunotherapy.

The aim of the present study was to establish cancer stem-like cell/cancer-initiating cell (CSC/CIC)-targeting immunotherapy. The CSC/CIC are thought to be essential for tumor maintenance, recurrence and distant metastasis. Therefore they are reasonable targets for cancer therapy. In the present study, we found that a heat shock protein (HSP) 40 family member, DnaJ (Hsp40) homolog, subfamily B, member 8 (DNAJB8), is preferentially expressed in CSC/CIC derived from colorectal cancer (CRC) cells rather than in non-CSC/CIC. Overexpression of DNAJB8 enhanced the expression of stem cell markers and tumorigenicity, indicating that DNAJB8 has a role in CRC CSC/CIC. A DNAJB8-specific cytotoxic T lymphocyte (CTL) response could be induced by a DNAJB8-derived antigenic peptide. A CTL clone specific for DNAJB8 peptide showed higher killing activity to CRC CSC/CIC compared with non-CSC/CIC, and CTL adoptive transfer into CRC CSC/CIC showed an antitumor effect in vivo. Taken together, the results indicate that DNAJB8 is expressed and has role in CRC CSC/CIC and that DNAJB8 is a novel target of CRC CSC/CIC-targeting immunotherapy.

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