The RARγ Oncogene: An Achilles Heel for Some Cancers

Abstract

Cancer “stem cells” (CSCs) sustain the hierarchies of dividing cells that characterize cancer. The main causes of cancer-related mortality are metastatic disease and relapse, both of which originate primarily from CSCs, so their eradication may provide a bona fide curative strategy, though there maybe also the need to kill the bulk cancer cells. While classic anti-cancer chemotherapy is effective against the dividing progeny of CSCs, non-dividing or quiescent CSCs are often spared. Improved anti-cancer therapies therefore require approaches that target non-dividing CSCs, which must be underpinned by a better understanding of factors that permit these cells to maintain a stem cell-like state. During hematopoiesis, retinoic acid receptor (RAR) γ is selectively expressed by stem cells and their immediate progeny. It is overexpressed in, and is an oncogene for, many cancers including colorectal, renal and hepatocellular carcinoma, cholangiocarcinomas and some cases of acute myeloid leukemia that harbor RARγ fusion proteins. In vitro studies suggest that RARγ-selective and pan-RAR antagonists provoke the death of CSCs by necroptosis and point to antagonism of RARγ as a potential strategy to treat metastatic disease and relapse, and perhaps provide a cure for some cancers.

Blockage of retinoic acid signaling via RARγ suppressed the proliferation of pancreatic cancer cells by arresting the cell cycle progression of the G1-S phase

“…In addition, our analysis of TCGA data showed that the patient prognosis correlated with RARγ expression but not with RARα expression. Like PDAC, prostate cancer cells also express RARα and RARγ, but the proliferation of the tumor cells has been reported to depend only on RARγ [34]. The authors mentioned that these were because RARα, which requires approximately 100-times higher levels of ATRA than RARγ, was not su ciently activated due to low levels of ATRA in prostate cancer tissues [34].…”

“…Like PDAC, prostate cancer cells also express RARα and RARγ, but the proliferation of the tumor cells has been reported to depend only on RARγ [34]. The authors mentioned that these were because RARα, which requires approximately 100-times higher levels of ATRA than RARγ, was not su ciently activated due to low levels of ATRA in prostate cancer tissues [34]. Previous studies have shown that PDAC tissues also had lower levels of ATRA than normal pancreatic tissues [13] as well as attenuated RA signaling activity [12].…”

Oncogenes and the Origins of Leukemias

“…Some AML patients' cells have RARγ fusion proteins. RARγ is often over-expressed in colorectal and renal cancer and RARγ promotes the growth of hepatocellular cancer xenografts in mice reviewed in [84]. Prostate cancer cells depend on RARγ activation for their survival; the use of a synthetic retinoid to antagonize RARγ kills prostate cancer CSC-like cells [85].…”

“…Prostate cancer cells depend on RARγ activation for their survival; the use of a synthetic retinoid to antagonize RARγ kills prostate cancer CSC-like cells [85]. Antagonizing all RARs kills breast cancer CSC-like cells and the CSCs that give rise to neurosphere-like structures from pediatric patients' primitive neuroectodermal tumors and astrocytoma [84]. The RARγ antagonist is, therefore, a promising new therapeutic for the above cancers.…”

Lessons to cancer from studies of leukemia and hematopoiesis

“…Antagonism of RARs was effective against other cancers. Antagonizing all RARs killed MCF7 and MDA-MB-231 breast cancer cell line cells and pediatric patients’ primitive neuroectodermal tumor and astrocytoma cells, including elimination of the CSCs that gave rise to neurospheres ( Brown and Petrie, 2021 ).…”