Recent clinicopathologic studies have shown that many prostatic adenonomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal nsduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markediy neuronal morphology. Also in LNCaP cells ultrtructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest incuding S-100, chromogranin A, pp60 , and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker ppWw, and in both cell lines expression ofKS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addiion to effects on lineage markers, cAMP treatment induced GI synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plastic in the lineag commitment of adenocarcinoma of the prostate. We have shown that cellpermeant cAMP analogue can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.In an effort to develop new anticancer drugs directed at unique aspects of prostate cancer biology, we have been studying the signal transduction pathways regulating the growth of human prostate adenocarcinoma cells in vitro. As reported previously, we found that addition of dibutyryl (db) cAMP to the androgen-independent prostate carcinoma cell line PC-3 causes induction of type (32 transforming growth factor (TGF-g32) mRNA, production of bioactive TGF-P2, and growth arrest (1).We have subsequently studied the effect of cAMP derivatives and phosphodiesterase inhibitors on the other two commonly available prostate carcinoma cell lines, DU 145 and LNCaP, as well as the highly metastatic variant of PC-3, PC-3-M, and found that all lines were growth inhibited by elevation of intracellular cAMP (data not shown). Data presented here demonstrate that in two ofthese lines, LNCaP and PC-3-M, elevation of intracellular cAMP induces permanent conversion from an epithelial to a neuronal morphology and that these cells express markers of the neuroendocrine phenotype. These data suggest that these cell lines, which are derived from metastatic adenocarcinoma of the prostate, contain or consist of multipotent cells capable of both neuroendocrine and epithelial differentiation.
Summary Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 has been demonstrated to be the proximate cause of a subset of thrombotic microangiopathic haemolytic anaemias (MAHA) typical for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary form; acquired deficiency has been attributed to presence of an autoantibody, which may represent a specific subset of MAHA best termed ‘autoimmune thrombotic thrombocytopenic purpura’. We describe a patient with relapsing TTP because of ADAMTS13 inhibitors, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine, staphylococcal protein A and splenectomy. The ADAMTS13 inhibitor titre remained elevated and clinical stability was only maintained by plasma exchange every 2–3 d over a period of 268 d. The patient then received rituximab therapy (eight doses of 375 mg/m2 weekly), during which she required five plasma exchanges in the first 10 d, two exchanges in the next 3 weeks, and none thereafter for 450 d and ongoing. The ADAMTS13 inhibitor titre decreased and enzyme activity increased. We compared this case with that of seven previously reported TTP cases also treated with rituximab; experience suggests that rituximab therapy deserves further investigation for patients with either refractory or relapsing TTP caused by ADAMTS13 inhibitors.
The distribution of the epidermal growth factor receptor (EGFR) in mouse testis was ascertained by immunocytochemical methodology using a polyclonal antibody (RK2) shown previously to recognize the cytoplasmic domain of the human (A431 cells), murine (Swiss 3T3 cells), and chicken (CK 109 cells) EGFR. Initial studies performed to determine the usefulness of this antibody as a probe of the murine EGFR in testis employed two murine cell lines, TM4 and MA10, of Sertoli cell and Leydig cell origin, respectively, in which a physiological response of EGF and specific binding of iodinated EGF has been demonstrated. Western blotting in membrane preparations of TM4 and MA10 revealed only one prominent band at 170 kDa. Immunocytochemical localization in TM4 and MA10 cells illustrated a plasma membrane distribution of the receptor. Western blotting of membrane fractions prepared from testis also revealed a specific band at 170 kDa. In the intact testis, the EGFR was immunolocalized specifically in Leydig cells and Sertoli cells only. These results suggest that the involvement of EGF action in spermatogenesis may occur at the level of the somatic components of the testes, principally in the Leydig and Sertoli cells.
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