Tumor cells are the site of erythropoietin synthesis in human renal cancers associated with polycythemia

Abstract

One to five percent of human renal cell carcinomas are associated with polycythemia. It is generally assumed that polycythemia results from the secretion of erythropoietin (Epo) by the malignant cells. However, there is no direct proof supporting this hypothesis. Three patients with typical renal adenocarcinoma and polycythemia were studied. All three exhibited high Epo serum levels as measured by radioimmunoassay (RIA). A strong Epo signal was observed on Northern blot analysis of total RNA extracted from the renal tumors. The Epo message seemed to be of normal size and no Epo gene rearrangement was observed with the restriction enzymes tested. Using the in situ hybridization technique, a significant labeling was constantly observed on the tumor cells. Immunohistochemical studies showed that these tumor cells, known to be of tubular origin, were labeled by an anti-cytokeratin antibody and therefore were of epithelial nature. Thus, this study demonstrated that malignant cells of tubular origin were able to produce Epo constitutively, whereas in the mouse hypoxic kidney, peritubular cells (probably capillary endothelial cells) were the major site of Epo synthesis.

Regulation of erythropoietin production

“…Moreover, overexpression of EPO mRNA has been shown in single cases of renal tumours. In situ hybridization revealed that accumulation of EPO mRNA occurs in epithelial tumour cells, but not interstitial cells of the tumour stroma [57]. The recent discovery of the role of the VHL protein in the regulation of HIF has renewed the interest in the expression of hypoxia-inducible genes in kidney tumours, since the majority of clear cell renal carcinomas -the most frequent type of renal cancer -are associated with mutations of the VHL gene [58].…”

Expression of erythropoietin and neuroendocrine markers in clear cell renal cell carcinoma

“…There is still confusion regarding the EPO‐producing cells and their regulation. However, the EPO‐producing cell seems to play a role in clear cell renal cell carcinoma (CCRCC) as 5% of patients with such tumours display polycythemia, which may be regarded as a parallel to hormone overproduction syndrome in patients with NETs . There are also other similarities between NETs and CCRCCs in that both tumour types tend to grow slowly, but nevertheless metastasize at an early stage .…”

Intrahepatic Cholangiocarcinoma Associated with High Procalcitonin, Hypercalcemia, Polycythemia and Leukocytosis

“…It is rarely reported in patients with cholangiocarcinoma. Polycythemia is also seen in other tumors like renal cell carcinoma, hemangioblastoma, uterine leiomyomas, and pheochromocytoma [16][17][18][19][20].…”