The discovery that tumor cells escape ceramide-mediated apoptosis by glycosylating ceramides and storing them as gangliosides (lactosylceramides with sialic acids) suggests that gangliosides (Ggs) may be valuable targets for diagnostic and therapeutic explorations. Stored Ggs are released into the tumor microenvironment and the circulation, where they suppress a variety of cell-mediated immune functions. While studying the tumor Ggs shed into the circulation after cryosurgical ablation of liver tumors, we observed that these shed gangliosides induced production of IgM specific to the tumor Ggs. Assay of sera from patients with early-stage sarcoma, colorectal carcinoma and melanoma confirmed the presence of anti-ganglioside IgMs characteristic of early tumors. These novel and serendipitous discoveries led us to evaluate whether specific anti-Gg lgM antibodies could serve as diagnostic and prognostic markers of subclinical prostate cancer (CAP). CaP progresses imperceptibly and is potentially curable when organ-confined. A noninvasive method for early detection would encourage more men to seek chemopreventive treatments before their CaP has metastasized beyond the prostate. Prostate-specific antigen (PSA) is widely used for diagnosing and monitoring CaP. However, serum PSA level does not increase significantly until tumor volume exceeds 1cc, and it is inversely related to a tumor's histologic grade. Moreover, benign prostatic hyperplasia (BPH) and prostatitis can falsely elevate serum PSA. By contrast, serum levels of anti-Gg IgM antibodies in healthy individuals decline with age and remain low (titer <50) above the age of 60. In CaP patients above 60 years of age, serum anti-Gg IgM antibodies, particularly anti-GD1a, are highly elevated, possibly due to release and sensitization of tumor Ggs. We have observed that serum IgM antibodies from CaP patients immunostained GM1b more strongly than GD1a, suggesting that GM1b may be more immunogenic in patients. We hypothesize that serum anti-GM1b and anti-GD1a IgM in patients with early-stage CaP (T1c) may represent potential markers for localized disease. Although anti-GM1b is not available from commercial sources, we have identified GM1b in large quantities in CaP cell lines. Therefore we will purify GM1b from CaP lines. We hypothesize that the anti-GM1b and anti-GD1a IgM could be more sensitive prognostic markers in patients with localized disease. We will determine their diagnostic potential with and without serum PSA for identifying patients with stage T1 CaP. 1. To isolate and purify CaP-associated ganglioside GMlb from PC3 and Du145 cell lines, and use this ganglioside to study anti-GM1b IgM antibody titers in sera of patients with localized CaP. 2. To evaluate the diagnostic potential of anti-GM1b and anti-GD1a IgM antibodies, with or without PSA, by assessing sera from patients with stage T1 CaP of various Gleason grades, sera from patients with BPH and prostatitis, and sera from age-matched healthy volunteers.
| Ravindranath, Mepur H; Yesowitch, Paul; Sumobay, Cindy et al. (2007) Glycoimmunomics of human cancer: current concepts and future perspectives. Future Oncol 3:201-14 |
| Ravindranath, Mepur H; Muthugounder, Sakunthala; Hannah, Maghasi R et al. (2007) Significance of endogenous augmentation of antiganglioside IgM in cancer patients: potential tool for early detection and management of cancer therapy. Ann N Y Acad Sci 1107:212-22 |
| Ravindranath, Mepur H; Muthugounder, Sakunthala; Presser, Naftali et al. (2005) Endogenous immune response to gangliosides in patients with confined prostate cancer. Int J Cancer 116:368-77 |
| Ravindranath, Mepur H; Muthugounder, Sakunthala; Presser, Naftali et al. (2004) Gangliosides of organ-confined versus metastatic androgen-receptor-negative prostate cancer. Biochem Biophys Res Commun 324:154-65 |
