Clear Cell Renal Cancer, a Tumour with Neuroendocrine Features Originating from the Erythropoietin-Producing Cell

Abstract

The dominating type of kidney cancer is the clear cell renal cell cancer (ccRCC), hitherto been thought to develop from proximal tubule cells. However, the ability of tubule cells to proliferate is at best controversial. ccRCCs show many peculiarities like erythrocytosis due to erythropoietin overproduction and a combination of early metastases and sometimes apparent dormancy and late recurrence, features in common with neuroendocrine tumours (NETs). We have shown that most ccRCCs express erythropoietin and the neuroendocrine marker neuron-specific enolase, and other neuroendocrine markers in a percentage of the cancers. Missense mutation in von Hippel–Lindau (VHL) factor is rather specific for ccRCC found in familial and sporadic forms. The function of VHL factor is together with other proteins to destroy hypoxia-inducible factors (HIFs), central in adaptation to hypoxia. Lack of functioning VHL factor results in continuous overstimulation of the erythropoietin-producing cell to release erythropoietin and parallelly to proliferate, and in long-term mutations and malignant transformation. Thus, ccRCC occurs about 30 years later in sporadic cases compared with familial von Hippel–Lindau syndrome, reflecting the time necessary for two versus one genetic change. Embryologically, there are many arguments favouring neural crest origin of the erythropoietin-producing cell.

Dysfunction of von-Hippel Lindau factor causes reduced degradation of HIF leading to renal cancer. Hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitors also lessen HIF destruction and could therefore increase renal cancer

“…It is, however, well-known that a small proportion of patients with clear cell renal cell cancer (CCRCC) has erythrocytosis and a larger part EPO production in the cancer cells ( Palapattu et al, 2002 ; Wiesener et al, 2007 ). In a study applying immunohistochemistry with high sensitivity we found that practically all CCRCCs expressed erythropoietin as well as the neuroendocrine marker neuron-specific enolase (NSE) ( Mjønes et al, 2017 ), the latter a marker with hitherto misrecognized reputation.We concluded that CCRCC (the dominating histological type of kidney cancer) ( Mjønes et al, 2017 ; Waldum et al, 2022 ) originated from the EPC. There are many features in CCRCC in common with neuroendocrine tumours ( Waldum et al, 2022 ).…”

“…In a study applying immunohistochemistry with high sensitivity we found that practically all CCRCCs expressed erythropoietin as well as the neuroendocrine marker neuron-specific enolase (NSE) ( Mjønes et al, 2017 ), the latter a marker with hitherto misrecognized reputation.We concluded that CCRCC (the dominating histological type of kidney cancer) ( Mjønes et al, 2017 ; Waldum et al, 2022 ) originated from the EPC. There are many features in CCRCC in common with neuroendocrine tumours ( Waldum et al, 2022 ). HIF is a major stimulator of EPO production, whereas von-Hippel Lindau factor is central in HIF degradation.…”

Renal neuroendocrine tumour with preoperative diagnostic dilemma

“…In another study, NSE expression was highest among tumours of neuroendocrine origin and ccRCC 10. Thus ccRCC may be a neuroendocrine tumour too, however, the nomenclature and classification of ccRCC remain yet to be modified 11…”

Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

“…Moreover, more tumors develop from NE cells than presently recognized. For instance, we have shown that the most prevalent type of kidney cancer, clear cell renal cell cancer (CCRCC), most likely originates from EPO cells ( 21 , 22 , 33 ). Clinically, these tumors exhibit similarities to NETs, including early metastases, low response to cytotoxic drugs, and, parallel to hormonal overstimulation in NETs, erythrocytosis in a subset of patients.…”

“…Clinically, these tumors exhibit similarities to NETs, including early metastases, low response to cytotoxic drugs, and, parallel to hormonal overstimulation in NETs, erythrocytosis in a subset of patients. They also share positivity for neuron-specific enolase (NSE) ( 33 , 34 ). NSE is a more specific neuroendocrine marker than ordinarily believed ( 34 ).…”