ABSTRACT
Most prostate cancers escape endocrine therapy by diverse mechanisms. One of them might be growth repression by androgen. We reported that androgen represses the growth in culture of MOP cells (a sub-line of LNCaP cells) and that of MOP cell xenografts, although tumor growth becomes androgen-independent (AI). Here we explore whether AI tumors contain androgen-responsive cells. ME carcinoma cells were established from AI tumors. The responses to androgen were examined by cell counting, DAPI labeling, flow cytometry, PSA immunoassay and tumor size follow-up. Androgen receptors (AR) were analyzed by western blotting and DNA sequencing. The pattern of responses of these cells to androgen was compared to that of MOP cells and that of JAC cells established from LNCaP-like MOP cells. R1881, a synthetic androgen: (1) repressed the growth of all the six ME cell lines obtained, MOP and JAC cells, (2) augmented the secretion of PSA, (3) induced spectacular cell bubbling/fragmentation and (4) blocked the cell cycle and induced a modest increase of apoptosis. All the androgen-repressed cells expressed the same level of mutated AR as LNCaP cells. In nude mice, the growth of ME-2 cell xenografts displayed transient androgen repression similar to that of MOP cells. In culture neither fibroblasts nor extra-cellular matrix altered the effects of R1881 on cell proliferation. These results demonstrate that androgen-independent tumors contain androgen-responsive cells. The apparent discrepancy between the responses to androgen of tumors and those of carcinoma cells in culture suggests that microenvironmental factors contribute to the androgen responsiveness of tumor cells in vivo. These modifications, albeit unspecified, could be suitable targets for restoring the androgen responsiveness of AI tumors.
Subject(s)
Androgens/pharmacology , Carcinoma/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Androgens/metabolism , Animals , Carcinoma/genetics , Cell Line, Tumor , Female , Fluorescent Antibody Technique, Indirect , Growth Inhibitors/metabolism , Growth Inhibitors/pharmacology , Humans , Male , Metribolone/metabolism , Metribolone/pharmacology , Mice , Mice, Nude , Neoplasm Transplantation , Prostatic Neoplasms/genetics , Time Factors , Transplantation, Heterologous , Xenograft Model Antitumor AssaysABSTRACT
Quantitative monitoring of imatinib mesylate (IM)-resistant, mutated BCR-ABL(+) cells during the follow-up of CML could be useful for optimizing therapeutic management. We retrospectively analyzed T315I mutated BCR-ABL clones throughout the CML history of two patients by nested-PCR-RFLP. At the time of progression, the T315I mutation represented 100% of the BCR-ABL transcripts. During follow-up, we showed that (i) despite a molecular response to IM, a high proportion of T315I transcripts were present (>85%) and predictive of relapse, (ii) interruption of IM and switching to other therapies resulted in a significant reduction in mutant transcript level while total BCR-ABL(+) transcripts remained stable.
