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.
Highlights
The stem cell theory of cancer states that most, if not all, cancers arise from a tissuespecific stem cell [1]
Evidence in support of the concept of Cancer “stem cells” (CSCs) is underpinned by investigative studies, in particular in acute leukemias that led to the characterization of leukemia stem cells (LSCs)
The different mutant proteins were observed to alter lineage-specific chromatin priming [64]. Another aspect to the importance of epigenetics in leukemia is the role of DNA methytransferases alongside all-trans retinoic acid (ATRA) in the regulation of expression Hox genes, which are critical for the proper maintenance of hematopoietic stem cells (HSC), as well as proliferation and survival of LSC [65]
Summary
The stem cell theory of cancer states that most, if not all, cancers arise from a tissuespecific stem cell [1]. When an oncogenic insult modifies one of the stem or progenitor cells that give rise to various types of mature tissue cells, it converts it into a cancer-initiating cell This cell is the origin of cancer, but more changes are needed before it, or an offspring of the cancer-initiating cell, becomes a cancer stem cell (CSC) [2]. Classic anti-cancer chemotherapy is effective against the dividing progeny of CSCs, but spares non-dividing CSCs. As early as 1999, a rare and quiescent subpopulation of primitive leukemia cells was isolated from samples from 6 patients with chronic-phase chronic myeloid leukemia (CML). As early as 1999, a rare and quiescent subpopulation of primitive leukemia cells was isolated from samples from 6 patients with chronic-phase chronic myeloid leukemia (CML) These leukemia stem cells (LSCs) were insensitive to even high doses of cytotoxic agents targeted against the cell cycle [3]. We examine evidence that supports the view that RARγ is an Achilles heel for some cancers
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