Armen G. Aprikian

Bombesin stimulates the motility of human prostate-carcinoma cells through tyrosine phosphorylation of focal adhesion kinase and of integrin-associated proteins.

Bombesin‐like peptides, including the mammalian homologue gastrin‐releasing peptides, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma (PCa) tissues and are likely to be related to the progression of this disease. In the present study, we show that bombesin enhances the migration of androgen‐independent PCa cells (PC‐3) in vitro, while not affecting their adhesion to extracellular matrix proteins. The bombesin‐increased motility of PC‐3 cells occurs through its receptor, and, as shown with inhibitors, it likely requires activation of both protein tyrosine kinases (PTKs) and protein kinases C (PKCs). Because the focal adhesion kinase pp125FAK plays a key role in adhesion/motility and is highly expressed in advanced PCa, we examined whether in PC‐3 cells bombesin signal transduction triggers the tyrosine phosphorylation of this PTK and of associated integrins and signaling proteins likely to be present in focal adhesion plaques. pp125FAK tyrosine phosphorylation was stimulated by bombesin and mimicked by PKC activation with the tumor‐promotor phorbol 12‐myristate‐13‐acetate (PMA). Moreover, this effect of bombesin on pp125FAK tyrosine phosphorylation requires the presence of both active PKC and cytoskeleton integrity since this signal was abolished by down‐regulating PKCs induced by prolonged PMA treatment or by PKC inhibition with GF 109203X, as well as by disruption of the cytoskeleton with cytochalasin D. We also show that bombesin increases the tyrosine phosphorylation of a 95‐kDa protein (pp95) which was co‐immunoprecipitated with the αv and β (3 and 5) subunits, forming integrin receptors with αv in PC‐3 cells. The protein pp95 is distinct from the endogenously tyrosine‐phosphorylated β3 subunit. In addition, upon bombesin treatment, the β1, β3 and β5 integrin subunits co‐immunoprecipitated with pp125FAK and major phosphotyrosine (pY)‐containing proteins of 125 and 68–70 kDa, likely corresponding to pp125FAK and paxillin. Together our data suggest that, in addition to PKC activation, tyrosine phosphorylation of pp125FAK and integrin‐associated proteins may play an important role in bombesin signaling, triggering the processes of PCa cell motility and invasion. Int. J. Cancer 72:498–504, 1997.

Renal carcinoid and horseshoe kidney: A frequent association of two rare entities—A case report and review of the literature

We report the case of a primary renal carcinoid tumor associated with a horseshoe malformation in a 43‐year‐old man who presented with testicular pain. The tumor was centrally located and purely solid and had features ascribed to hindgut neuroendocrine neoplasia. The relative risk of developing a carcinoid tumor in a horseshoe kidney is estimated to be ×82. J. Surg. Oncol. 1998;68:113–119.

Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 for Prostate Cancer Detection in Patients Undergoing Prostate Biopsy

PURPOSEnLaboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy.nnnMATERIALS AND METHODSnA total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions.nnnRESULTSnMean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3.nnnCONCLUSIONSnOur data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.

Serum insulin‐like growth factor (IGF)‐1 and IGF‐binding protein‐3 do not correlate with Gleason score or quantity of prostate cancer in biopsy samples

To examine the relationship of serum insulin‐like growth factor (IGF)‐1 and IGF binding protein‐3 (IGFBP‐3) with histological cancer characteristics in men undergoing transrectal ultrasonography (TRUS)‐guided biopsy.

Phase I Clinical Trial of Everolimus Combined with Trimodality Therapy in Patients with Muscle-Invasive Bladder Cancer

Background: Local control following trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) requires further optimization. Objective: Evaluating the biologic endpoint, feasibility, and toxicity of integrating everolimus to TMT in patients with MIBC. Methods: This was a phase I trial in patients with MIBC who were not surgical candidates or who refused cystectomy. Following maximal transurethral tumor resection, patients were treated by radiotherapy (50u200aGy/20 fractions), gemcitabine (100u200amg/m2/weekly) and escalating doses of everolimus (2.5–5.0u200amg/day). Everolimus was given daily for one month prior to radiation, during treatment, and one month post-radiation. Toxicity assessment followed the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. Biologic endpoint with downregulation of phospho-S6 (pS6) was assessed using immunohistochemistry. Local response was evaluated with imaging and bladder biopsy post-therapy. Results: 10 patients were recruited; 8 males, 2 females. Median age was 78 years (range: 63–85). Four patients entered everolimus 2.5u200amg cohort. Six other patients entered everolimus 5.0u200amg cohort. Toxicities were encountered in 2 patients (Grade I), 6 patients (Grade II), 9 patients (Grade III) and 1 patient (Grade IV), with some experiencing more than one toxicity. Most Grade III and IV toxicities were encountered from everolimus alone prior to combination testing. Trial was terminated early due to toxicity. Interestingly, 6/10 patients (60%) achieved a complete response with negative post-treatment biopsies. Significant decrease of pS6 was demonstrated post-therapy (pu200a=u200a0.03). Conclusions: Although combining everolimus with TMT achieved a biological endpoint and complete response in a significant number of patients with MIBC and negative prognostic factors, it was associated with unacceptable increased toxicity.