Cancer pain relief achieved by disrupting tumor-driven semaphorin 3A signaling in mice.

Cancer-induced bone pain (CIBP) is the most common pain arising from cancer and is inadequately managed with current standard therapeutics. While the etiology of CIBP remains to be fully elucidated, increasing evidence suggests that CIBP is uniquely complex. We tested whether semaphorin 3A (Sema3A) signals were involved in the development of CIBP in mice. The mouse model employed for CIBP - mice inoculated with Lewis lung carcinoma (LLC) cells injected into the femur intramedullary space - showed progressive decline in the weight bearing of the ipsilateral hind limb. The LLC cell inoculation resulted in a progressive increase in Sema3A mRNA expression over time and an increase in the number of Sema3A-immunoreactive cells in the ipsilateral femur. To define the role of Sema3A in development of CIBP, we employed a lentiviral expression system to establish a stable LLC cell line expressing scrambled shRNA for the control group (LLC/scramble) and shRNAs directed against Sema3A mRNA for the loss-of-function group (LLC/shSema3A). Inoculation of LLC/shSema3A did not cause upregulation of Sema3A mRNA expression and proliferation of the inoculated cells in the femur compared to that in mice inoculated with LLC/scramble. Mice inoculated with LLC/shSema3A, but not LLC/scramble, showed an attenuation of the significant decline in the weight bearing of the ipsilateral hind paw. Our findings indicate that Sema3A serves as a potential therapeutic target for CIBP.

The Effects of the Tumor Mass Size Inoculated in Immunologically Competent Balb/c Mice on Delayed-type Hypersensitivity Response

BACKGROUND: Based on outstanding progresses in animal experiments, vaccines for some human tumors have been developed. However, clinical effects of these vaccines have been far below than expected. This discrepancy might come from differences between animal models and human patients with respect to immunocompetency. The immune status of mice after tumor inoculation has not been well studied, which make us cautious in interpreting and applying the results from mice to human. We evaluated cell-mediated immune responses in mice after tumor cell inoculation. METHODS: Mice were inoculated with TA3Ha, CT26, or 4T1. Delayed-type hypersensitivity (DTH) responses were induced 2-4 weeks after inoculation using 2,4-dinitro-1-fluorobenzene as an antigen. The relationships between the severity of DTH responses and the duration of tumor inoculation or the size of tumor mass were analyzed. RESULTS: In TA3Ha groups, DTH response was elevated 2 weeks after inoculation, but depressed after 4 weeks, compared to the control group. When analyzed based on the sizes of tumor masses elicited, DTH responses were inversely related to the mass size, especially in those greater than 10 mm in diameter. In CT26 groups, while the duration after inoculation did not affect the severity of DTH responses, those with large mass showed depressed responses regardless the duration of inoculation. 4T1 cells grew so slowly that the size of tumor mass was small even 4 weeks after inoculation, and this group showed much higher DTH responses compared to that of tumor-free group. CONCLUSION: At least in an experimental setting where tumor model was induced by inoculating tumor cell lines into immunologically competent mice, the host immune response was elevated in early stage, and then depressed in late stage when the mass grew over a critical size.

SST-2 tumor inoculation is a useful model for studying the anti-tumor immune response in SHR rats.

OBJECTIVE: The purpose of the present study was to investigate the relation between the dose of tumor cell inoculation (especially the doses less than minimum required to evoke tumor growth) and the anti-tumor immune system, particularly lymphoblast formation and cytotoxic activity of lymphcytes. METHOD: We inoculated rats with various doses of SST-2 tumor cells and examined natural killer (NK) cell activity and lymphoblast formationin vitro. RESULT: The results showed that the cytotoxicities against SST-2 cells and lymphoblast formation of lymphocytes were enhanced by small dose inoculation of tumor cells that could not induce tumor growth. CONCLUSION: It was suggested that was lymphocutes play an important role as an anti-tumor immune system at small doses of tumor inoculation, which appears to reflect an early stage of tumor growthin vivo. It was also suggested that SST-2 tumor inoculation might be a useful model for studying the anti-tumor immune response in SHR rats.

SST-2 Tumor Inoculation is a Useful Model for Studying the Anti-Tumor Immune Response in SHR Rats

Objective: The purpose of the present study was to investigate the relation between the dose of tumor cell inoculation (especially the doses less than minimum required to evoke tumor growth) and the anti-tumor immune system, particularly lymphoblast formation and cytotoxic activity of lymphcytes. Method: We inoculated rats with various doses of SST-2 tumor cells and examined natural killer (NK) cell activity and lymphoblast formation in vitro. Result: The results showed that the cytotoxicities against SST-2 cells and lymphoblast formation of lymphocytes were enhanced by small dose inoculation of tumor cells that could not induce tumor growth. Conclusion: It was suggested that was lymphocutes play an important role as an anti-tumor immune system at small doses of tumor inoculation, which appears to reflect an early stage of tumor growth in vivo. It was also suggested that SST-2 tumor inoculation might be a useful model for studying the anti-tumor immune response in SHR rats.

SST-2 tumor inoculation is a useful model for studying the anti-tumor immune response in SHR rats

<p><b>OBJECTIVE</b>The purpose of the present study was to investigate the relation between the dose of tumor cell inoculation (especially the doses less than minimum required to evoke tumor growth) and the anti-tumor immune system, particularly lymphoblast formation and cytotoxic activity of lymphcytes.</p><p><b>METHOD</b>We inoculated rats with various doses of SST-2 tumor cells and examined natural killer (NK) cell activity and lymphoblast formationin vitro.</p><p><b>RESULT</b>The results showed that the cytotoxicities against SST-2 cells and lymphoblast formation of lymphocytes were enhanced by small dose inoculation of tumor cells that could not induce tumor growth.</p><p><b>CONCLUSION</b>It was suggested that was lymphocutes play an important role as an anti-tumor immune system at small doses of tumor inoculation, which appears to reflect an early stage of tumor growthin vivo. It was also suggested that SST-2 tumor inoculation might be a useful model for studying the anti-tumor immune response in SHR rats.</p>