International Conference on Oral, Mouth and Throat Cancer August 15-17, 2016 Portland, Oregon, USA

Dr Ueyama has completed his PhD from Okayama University in 1990 and works for Yamaguchi University Medical Scholl in oral and maxillofacial surgern. He is a medical specialist in oral cancer.

The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs. Here, we examined whether introduction of defined reprogramming factors (Oct4, shp53, Sox2, Klf4, l-Myc and Lin28) into HSC2 oral cancer cells could transform the HSC2 into HSC2 with CSCs properties. Methods: We introduced the defined reprogramming factors into HSC2 oral cancer cells via episomal vectors by electroporation method to generate transfectant cells. We investigated the malignant properties of the transfectant cells by cell proliferation assay, migration assay, wound healing assay, sphere formation assay, chemosensitivity and radiosensitivity assay in vitro; and also examined the tumorigenic potential of the transfectants in vivo. Results: The transfectant cells (HSC2/hOCT3/4-shp53-F, HSC2/hSK, HSC2/hUL, HSC2/hOCT3/4-shp53-F+hSK, HSC2/hOCT3/4-shp53-F+hUL, HSC2/hSK+hUL, HSC2/hOCT3/4-shp53-F+hSK+hUL) displayed a malignant phenotype in culture and form tumors on the back of nude mice more efficiently than parental HSC2 and control HSC2/EGFP transfectant cells. They exhibited increased resistance to chemotherapeutic agents; 5-fluorouracil, cisplatin, docetaxel, trifluorothymidine, zoledronic acid, cetuximab, bortezomib and radiation when compared with HSC2 and HSC2/EGFP. Among all the transfected cells, HSC2/hOCT3/4-shp53-F+hSK+hUL cell containing all of the reprogramming factors showed the most aggressive and malignant properties and presented the highest number of spheres in the culture medium containing human recombinant fibroblast Growth Factor-2 (FGF-2) and epidermal Growth Factor (EGF). Conclusion: These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs.

Dr. Tomihara received his Ph.D. degree in 2006 from Sapporo Medical University, working on immune gene therapy by adenovirus vector. He then moved to Cancer Therapy and Research Center (CTRC) at The University of Texas Health Science Center at San Antonio (UTHSCSA) to work with Dr. Shin as a post-doctoral fellow. He obtained an assistant professor position in 2013 in the Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, where he started independent research on cancer immunology.

Cancer is often associated with destruction in both the humoral and cellular immune responses, and this phenomenon has been suggested to be attributed by the alteration of several cell populations. Myeloid derived suppressor cells (MDSC), one of the myeloid lineage cells, has been shown to be accumulated within either the tumor microenvironment or peripheral blood which collates with the impairment of immune response and the promotion of tumor growth. However, this cell type is a heterogeneous cell population that can be altered by type of the tumor and its anatomical location, and the characterization of their function during cancer has not been still fully elucidated. Here, we show that MDSCs are increased in the spleen, bone marrow, peripheral blood and the tumor site in the murine oral squamous cell carcinoma-bearing mice, however, the phenotype and function of the cells from each origin are not consistent. MDSCs in the tumor site, but not in the spleen, bone marrow, and peripheral blood exhibit increased expression of PD-L1 on their cell surface and strong immune suppression against in vitro cocultured T cells through the expression of PD-L1, indicating that MDSCs accumulated in tumor bearing host may not be originally immune suppressive, however, they could be phenotypically and functionally altered by the influence of tumor-derived factors and converted into immune suppressive cells. Our results suggest that targeting MDSCs would be more efficient strategy for cancer treatment in combination with PD-L1 blocking.

Dr. Noguchi’s career started from a technical officer, the Department of Oral Surgery, National Medical Center in Tokyo (1983-87). He headed for the Department of Oral & Maxillofacial Surgery, Sapporo Medical University School of Medicine (1987-2005), where he had pursued his career as an oncological surgeon for oral cancer: Resident (1987-88), Assistant 1988-1997), Assistant Professor (1997-2002), Associate Professor (2002-2005). During that time he received PhD degree from Sapporo Medical University by working in research on oral cancer (1993), Professional Oral and Maxillofacial Surgeon (1994) and Diplomate (Consultant) of Oral and Maxillofacial Surgeon, Board Certified of Japanese Society of Oral and Maxillofacial Surgeons (1999). He has currently organized the Department of Oral & Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama as a professor and chair since 2007.

Regulatory T cells (Tregs) have been demonstrated to inhibit inflammatory bone destruction through suppressing osteoclast differentiation in the bone microenvironment of inflammatory diseases. However, very little work has been done to characterize Tregs in the microenvironment of cancer bone invasion. We herein demonstrate the mechanism of interaction between Tregs and osteoclasts in a murine model of oral cancer to elucidate the role of Tregs in the bone invasion of oral cancer. Methods: SCCVII mouse oral squamous cell carcinoma cells were administered into the right masseter region of a C3H/HeN mouse. After 14 days of tumor inoculation, mice were sacrificed and Tregs were purified from the tumors. Tregs were then cocultured with bone marrow CD11b+ cells in the absence or presence of RANKL and M-CSF for 4 days. Secreted tartrate-resistant acid phosphatase (TRACP) 5b was determined as a marker of osteoclast number. Results: Attenuation of osteoclast-derived TRACP5b was observed in the coculture of tumor derived Tregs and bone marrow CD11b positive cells, and this attenuation of TRACP5b was ameliorated by neutralization of cytotoxic T-lymphocyte-associated antigens-4 (CTLA-4). Conclusions: These results indicate that Tregs may play a protective role in bone invasion of oral cancer via suppression of osteoclast differentiation, and CTLA-4 may be a key regulator for the suppression of osteoclasts by Tregs in oral cancer.

Seung Hee Choi has completed her PhD and postdoctoral studies from University of Michigan School of Nursing. She is an assistant professor of nursing at Michigan State University. She has published more than 10 papers in peer-reviewed journals.

The Institute of Medicine (IOM) report, “Unequal Treatment,” which defines disparities as racially based, indicates that disparities in cancer diagnosis and treatment are less clear. While a number of studies have acknowledged cancer disparities, they have limitations of retrospective nature, small sample sizes, inability to control for covariates, and measurement errors. To examine disparities as predictors of survival among newly diagnosed head and neck cancer patients recruited from 3 hospitals in Michigan, USA, while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). Longitudinal data were collected from newly diagnosed head and neck cancer patients (N=634). The independent variables were median household income, education, race, age, sex, and marital status. The outcome variables were overall, cancer-specific, and disease-free survival censored at 5 years. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models were performed to examine demographic disparities in relation to survival. Five-year overall, cancer-specific, and disease-free survival were 65.4% (407/622), 76.4% (487/622), and 67.0% (427/622), respectively. Lower income (HR, 1.5; 95% CI, 1.1–2.0 for overall survival; HR, 1.4; 95% CI, 1.0–1.9 for cancer-specific survival), high school education or less (HR, 1.4; 95% CI, 1.1–1.9 for overall survival; HR, 1.4; 95% CI, 1.1–1.9 for cancer-specific survival), and older age in decades (HR, 1.4; 95% CI, 1.2–1.7 for overall survival; HR, 1.2; 95% CI, 1.1–1.4 for cancer-specific survival) decreased both overall and disease-free survival rates. A high school education or less (HR, 1.4; 95% CI, 1.0–2.1) and advanced age (HR, 1.3; 95% CI, 1.1–1.6) were significant independent predictors of poor cancer-specific survival. Low income, low education, and advanced age predicted poor survival while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). Recommendations from the Institute of Medicine’s Report to reduce disparities need to be implemented in treating head and neck cancer patients.