Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer

Background Mesothelin has attracted much interest as a tumor specific antigen; it has been reported to promote tumor development and to be a good target for cancer treatment. Most studies to date have used human mesothelin in immunocompromised mice. Since these models do not allow for study of the natural immune response to mesothelin expressing tumors, we have undertaken the characterization of mouse mesothelin so the effects of this protein can be assessed in immunocompetent mouse strains. Methods We analyzed mouse mesothelin expression, tissue distribution, shedding and biochemistry. In addition we constructed stable mesothelin overexpressing lines of the pancreatic cancer line Panc02 by two methods and tested them for growth and tumorigencity in vitro and in vivo. Results We show here that mouse mesothelin is similar to human mesothelin in biochemical characteristics, tumor expression and tissue distribution, suggesting the mouse may be a suitable model for study of mesothelin. Stable overexpression of mesothelin in a pancreatic cancer cell line did not increase cell proliferation or anchorage-independent growth in vitro, suggesting that mesothelin is not necessarily a tumor progression factor. Surprisingly overexpression of mesothelin inhibited tumor formation in vivo in immunocompetent mice. Conclusion The mouse may be a good model for studying mesothelin in the context of an intact immune response. Mesothelin is not necessarily a tumor progression factor, and indeed mesothelin overexpression inhibited tumor growth in immunocompetent mice

Development of improved therapeutic mesothelin-based vaccines for pancreatic cancer

Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system

Looking Backward, Looking Forward: MLA Members Speak

In 1997 I was asked to organize humanities outreach activities at the University of California, Irvine. The result was the formation of Humanities Out There (HOT). In our workshops, faculty members and graduate students supervise teams of undergraduates in order to take the methods and materials of the university into the larger community.I believe that programs like these will  become increasingly important in the next century, as economic, cultural, and educational divisions deepen in the wake of the demise of affirmative action and as the humanities fight to define their missions in a world driven by technology and its discontents. In this brave new world, what I call the new outreach may have a role to play in responding to social crises as they are visited on the life of the university. The new outreach will be driven by intellectual content, not public relations.It will take its orientation from the faculty rather than administrators. It will engage all the research disciplines rather than remain the purview of education departments. It will be integrated into the professional lives of its participants rather than rely on the spirit of volunteerism alone

Looking Backward, Looking Forward: MLA Members Speak

In 1997 I was asked to organize humanities outreach activities at the University of California, Irvine. The result was the formation of Humanities Out There (HOT). In our workshops, faculty members and graduate students supervise teams of undergraduates in order to take the methods and materials of the university into the larger community.I believe that programs like these will  become increasingly important in the next century, as economic, cultural, and educational divisions deepen in the wake of the demise of affirmative action and as the humanities fight to define their missions in a world driven by technology and its discontents. In this brave new world, what I call the new outreach may have a role to play in responding to social crises as they are visited on the life of the university. The new outreach will be driven by intellectual content, not public relations.It will take its orientation from the faculty rather than administrators. It will engage all the research disciplines rather than remain the purview of education departments. It will be integrated into the professional lives of its participants rather than rely on the spirit of volunteerism alone