Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models.

BACKGROUND: Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood. METHODS: Lymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. RESULTS: Rapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines. CONCLUSIONS: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR-2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes.

Curcumin inhibits UV radiation-induced skin cancer in SKH-1 mice.

OBJECTIVE: As skin cancer incidence increases, research has focused on novel chemopreventive agents that inhibit tumor formation. In prior experimentation, curcumin, a naturally occurring food substance and anticarcinogenic agent, inhibited cutaneous squamous cell carcinoma xenograft growth. We hypothesize curcumin will inhibit UVB radiation-induced skin cancer growth in mice, approximating a human chemopreventive model. STUDY DESIGN: Randomized experimental animal and laboratory study. SETTING: Louisiana State University Health Sciences Center-Shreveport, Louisiana. SUBJECTS AND METHODS: SKH-1 mice were pretreated with oral or topical curcumin or oral or topical control (n = 11/group) for 14 days. Mice received UVB radiation 3 times weekly for 24 weeks or were not radiated. Number of tumors formed and time to tumor onset for each mouse were recorded through tumor harvest after week 24. Tumor multiplicity and time to tumor onset were compared. RESULTS: Time to tumor onset was significantly shorter in control mice compared to mice receiving either oral (P = .025) or topical (P = .015) curcumin. A significant difference in the average number of tumors formed per mouse was seen, as fewer tumors were formed in the oral curcumin (P = .01) and topical curcumin (P = .01) groups, compared with respective controls. No significant difference in average number of tumors per mouse was seen between oral and topical curcumin (P = .56), suggesting that both routes were equally effective. CONCLUSION: Curcumin appears to inhibit skin cancer formation and prolong time to tumor onset when administered by either an oral or topical route. These data suggest that curcumin may have chemopreventive potential against skin cancer, necessitating future experimentation with human subjects.

Comorbid predictors of poor response to chemoradiotherapy for laryngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: To investigate whether a correlation exists between medical comorbidities and disease control following primary therapy of laryngeal squamous cell carcinoma. STUDY DESIGN: Retrospective medical record review. METHODS: A retrospective chart review was performed on patients diagnosed with laryngeal carcinoma between 1997 and 2011. The Adult Comorbidity Evaluation 27 (ACE 27) index was used to evaluate severity of comorbid health. Ten-year disease-free survival rates and median disease-free intervals were calculated, and significant associations between disease recurrence and comorbid factors were determined using the log-rank test. Independent significant risk factors for disease recurrence were determined with the Cox proportional hazard regression model. RESULTS: Of the 181 patients identified, 121 were treated nonsurgically with either primary radiotherapy (XRT) (49%) or chemoradiotherapy (CRT) (51%). Sixty patients (50%) experienced recurrence of their disease. The 10-year disease-free survival rate was 23.8%, and the median disease-free survival was 58 months (95% confidence interval, 12-108 months). Factors observed to be significantly associated with recurrence within 10 years after treatment were renal disease (P < .01), pulmonary disease (P < .01), malnutrition (P < .01), T size (P < .01), stage (P = .02), and ACE 27 Index (P < .01). Independent significant risk factors for recurrence were malnutrition (P < .01), T stage (P = .01), and ACE 27 (P < .01). Adjusted hazard ratios were 1.43 for T stage, 2.58 for ACE 27, and 2.15 for malnutrition. CONCLUSIONS: The results of this study demonstrate that there is a significant association between increased comorbidity and recurrent disease in laryngeal carcinoma treated with XRT/CRT. The consideration of comorbid health in primary treatment planning may improve the success and survival of patients with laryngeal squamous cell carcinoma.

Topical curcumin-based cream is equivalent to dietary curcumin in a skin cancer model.

Skin squamous cell carcinoma (SCC), the most common cancer in the USA, is a growing problem with the use of tanning booths causing sun-damaged skin. Antiproliferative effects of curcumin were demonstrated in an aggressive skin cancer cell line SRB12-p9 (P < 0.05 compared to control). Topical formulation was as effective as oral curcumin at suppressing tumor growth in a mouse skin cancer model. Curcumin at 15 mg administered by oral, topical, or combined formulation significantly reduced tumor growth compared to control (P = 0.004). Inhibition of pAKT, pS6, p-4EBP1, pSTAT3, and pERK1/2 was noted in SRB12-p9 cells post-curcumin treatment compared to control (P < 0.05). Inhibition of pSTAT3 and pERK1/2 was also noted in curcumin-treated groups in vivo. IHC analysis revealed human tumor specimens that expressed significantly more activated pERK (P = 0.006) and pS6 (P < 0.0001) than normal skin samples. This is the first study to compare topical curcumin to oral curcumin. Our data supports the use of curcumin as a chemopreventive for skin SCC where condemned skin is a significant problem. Prevention strategies offer the best hope of future health care costs in a disease that is increasing in incidence due to increased sun exposure.