losartan-potassium and Adenocarcinoma--Clear-Cell

Signalling by erythropoietin (EPO) is increasingly recognised as a relevant mechanism in tumour biology, potentially leading to enhanced proliferation, angiogenesis and therapy resistance. Paraneoplastic polycythemia by cancerous overproduction of EPO is a rare event, but most frequently seen in patients with renal cell carcinoma (RCC). The majority of clear cell RCC displays a strong activation of the transcription factor regulating EPO, the Hypoxia-inducible Factor (HIF). Therefore, it is unclear why only a small minority of patients develop polycythemia. We studied 70 RCC for EPO gene and HIFalpha isoform expression. 34% of all RCC showed expression of EPO mRNA in RNase protection assays, which were almost exclusively of the clear cell type. Only 1 patient presented with polycythemia. In situ hybridisation revealed that expression of EPO was in the tumour cells. Expression of EPO mRNA was always associated with activation of HIF, which could involve HIF-1alpha and/or HIF-2alpha. The frequency of EPO gene expression in RCC is therefore much higher than the prevalence of polycythemia. Furthermore, activation of HIF appears necessary for EPO gene expression in RCC, but is clearly not the only determinant. Further to the reported expression of EPO receptors in tumour tissues, the finding of widespread expression of EPO in RCC supports the recent notion of an involvement of this system in paracrine or autocrine effects of tumour cells.

Topics: Adenocarcinoma, Clear Cell; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Cell Line, Tumor; Erythropoietin; Gene Expression Regulation, Neoplastic; Germany; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; In Situ Hybridization; Kidney Neoplasms; Paraneoplastic Syndromes; Polycythemia; Prevalence; Ribonucleases; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured; Up-Regulation

Clear cell renal cell carcinoma (CCRCC) is the most common renal carcinoma and it is often associated with von Hippel-Lindau disease (VHL) gene mutations. CCRCCs with VHL mutations demonstrate hypoxia-inducible factor (HIF) overexpression as well as increased expression of vascular endothelial growth factor (VEGF). Recently, the erythropoietin (Epo) has been found to be upregulated in renal and other tumors associated with VHL disease. Furthermore, Epo and Epo receptor (EpoR) coexpression has also been reported in these tumors. The results provided strong evidence that an autocrine loop is involved in tumorigenesis in VHL disease. We investigated whether Epo and EpoR coexpression also occurs in sporadic CCRCC. Fifty-four sporadic CCRCCs were analyzed. VHL gene mutations were detected in 30 out of 54 tumors. Coexpression of Epo and EpoR was detected in 50 out of 54 tumors regardless of their VHL mutation status. The results suggest that coexpression of Epo and EpoR plays an important role in tumorigenesis of sporadic CCRCC.

Topics: Adenocarcinoma, Clear Cell; Amino Acid Substitution; Base Sequence; Carcinoma, Renal Cell; Codon; DNA Primers; Erythropoietin; Humans; Kidney Neoplasms; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction

Erythropoietin (Epo), which is induced by hypoxia, controls erythropoiesis and protects neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, and resistance to therapy. The authors recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervical carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas.. The authors characterized the expression of Epo, EpoR, hypoxia-inducible factor (HIF)-1alpha, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemical methods using endometrial carcinoma samples from 107 women and benign endometrial samples from 59 women in various phases of the menstrual cycle. They then analyzed potential correlations of Epo and EpoR immunostaining and clinicopathologic tumor features with outcome.. In benign endometrial tissue samples, Epo and EpoR expression increased over the course of the cycle, with the highest levels observed in the late secretory phase. Epo expression in benign endometrial samples showed a negative correlation with ER and PR expression. The authors found Epo and EpoR expression in 95.3 % and 100% of endometrial carcinoma samples, respectively. Increased EpoR, but not Epo, expression in tumors was associated with advanced-stage disease, lymphovascular invasion, lymph node metastasis, and loss of ER expression. Increased Epo expression was observed in perinecrotic tumor regions in a pattern similar to the HIF-1alpha expression pattern. Increased Epo expression was significantly associated with adverse clinical outcome on both univariate and multivariate analysis.. Hypoxia-inducible autocrine Epo signaling in endometrial carcinoma may contribute to tumor progression and increased aggressiveness. Increased Epo expression in endometrial carcinomas may be an independent prognostic and/or predictive factor.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Aged, 80 and over; Cell Hypoxia; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Endometrium; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Lymphatic Metastasis; Menstrual Cycle; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Receptors, Erythropoietin; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Transcription Factors

We reported recently that normal human, rat, and mouse tubular cells express authentic erythropoietin-receptors (EPO-R) through which EPO stimulates mitogenesis. The present study examines whether EPO could elicit such a proliferative and thereby potentially detrimental response in cells of human renal-cell carcinoma (RCC).. Nephrectomy samples were screened from patients with RCC (one chromophilic, two clear cell) as well as cell lines of human (Caki-2, 786-0) and mouse (RAG) renal adenocarcinomas for expression of EPO-R transcripts and protein. Cells were further tested for specific 125I-EPO binding and mitogenic response to EPO.. Authentic EPO-R transcripts and protein (approximately 72 kD) were detected in renal tumors and cell lines. Tumors showed low-level EPO expression, while cell lines did not. In cells, specific 125I-EPO binding to a single class of EPO-R (apparent Kd 1. 3 to 1.4 nmol/L, Bmax 2.2 to 2.6 fmol/mg protein) was observed. EPO stimulated cell proliferation dose dependently, and the individual mitogenic effects of either EPO or 10% newborn calf serum were markedly amplified when both were coadministered.. These data are the first to demonstrate, to our knowledge, that human RCCs express EPO-R message and protein and that receptor activation stimulates their proliferation in vitro. If these mitogenic effects of EPO are also operative in patients with RCC, endogenous EPO or its administration for the treatment of anemia could potentially hasten proliferation of renocellular malignancies.

Topics: Adenocarcinoma, Clear Cell; Anemia; Animals; Carcinoma, Renal Cell; Cell Division; Erythropoietin; Gene Expression; Humans; Iodine Radioisotopes; Kidney Neoplasms; Kidney Tubules, Proximal; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Middle Aged; Mitogens; Neovascularization, Pathologic; Receptors, Erythropoietin; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; von Hippel-Lindau Disease