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| H. Barton Grossman, MD
Research Interests:
Bladder neoplasms, integrins, connexins, biological tumor markers |
The primary focus of my laboratory is the diagnosis and treatment of bladder cancer. Bladder cancer occurs in an organ that is readily accessible through minimally invasive techniques and is an excellent model for studying the diagnosis and treatment of solid tumors. Specimens for cytologic evaluation (voided urine and bladder barbotage) are easily obtained, and supplemental information can be acquired through visual examination, biopsy, physical examination, and radiographic studies.
My laboratory has developed several monoclonal antibodies that bind to bladder cancer-related antigens. One of these, DD23, is now being used clinically for the detection of this disease. Another antibody, BQ16, binds to the alpha6 integrin subunit. We have demonstrated that overexpression of the alpha6beta4 integrin in bladder cancer is associated with a decreased survival rate. We anticipate that ongoing studies will confirm this initial observation. This finding led us to explore other molecules that mediate intercellular communication. Connexins are a family of genes that encode proteins that form intercellular channels, known as gap junctions, that mediate intercellular communication by passing small molecules to the cytoplasm of adjacent cells. We demonstrated that decreased expression of connexin 26 mRNA occurred in our bladder cancer cell lines and was associated with a loss of functional gap junctions. We recently demonstrated that transfection of the connexin 26 gene restores gap-junctional communication and increases the bystander effect with simultaneous HSVtk gene therapy. Ongoing experiments with connexin 26 gene therapy in a nude mouse model with human bladder cancer cell lines are exploring the role of this gene as a tumor suppressor.
Progression of bladder cancer is associated with a loss of chromosome 10. Mutated in multiple advanced cancers-1/phosphatase and tensin homologue deleted on chromosome 10 (MMAC1/PTEN) has been identified as a tumor suppressor gene and is mapped to chromosome band 10q23. Although somatic mutations or deletions of MMAC1/PTEN have been found in bladder cancer as well as other neoplasms, the molecular and functional analyses of MMAC1/PTEN in bladder cancer have been limited. We showed that MMAC1/PTEN suppressed tumor growth in human bladder cancer cell lines and also demonstrated that gene therapy with MMAC1/PTEN abrogated expression of phosphorylated Akt/PKB and restored doxorubicin sensitivity in a doxorubicin-resistant bladder cancer subline. We will continue to explore these in vitro observations in an orthotopic in vivo murine model.
Upregulation of cyclooxygenase 2 (COX-2) has been recently identified as an early event in bladder cancer and as a target for chemoprevention. In collaboration with Dr. Anita Sabichi (Department of Clinical Cancer Prevention), a multiinstitutional clinical trial of COX-2 for the prevention of bladder cancer recurrence has been initiated. The evaluation of COX-2 and its mechanisms of action are being explored in vitro and in vivo.
Selected Publications
Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY, Luthra R, Logothetis C, von Eschenbach AC, Grossman HB, Benedict WF, Batsakis JG. Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: Implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene 18:1185-1196, 1999
Grossman HB, Dinney CPN. Markers of bladder cancer. State of the art. Urologic Oncology 5:3-10, 2000
Grossman HB, Lee C, Bromberg J, Liebert M. Expression of the alpha6beta4 integrin provides prognostic information in bladder cancer. Oncol Rep 7:13-16, 2000
Slaton JW, Swanson DA, Grossman HB, Dinney CP.. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 162:710-714, 1999
Tsihlias J, Grossman HB. The utility of fibrin/fibrinogen degradation products in superficial bladder cancer. Urol Clin North Am 27:39-46, 2000
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