On 2015 Jan 24, Madhusudana Girija Sanal commented:

How cancer stem cells may originate-the three hit hypothesis-the importance of epigenetic hit!

There are thousands (if not millions) of dangerous cancer associated mutations in every "healthy" human being. However, only a few get cancer. First of all one mutation may not lead to cancer, but two or more hits (the classic two hit hypothesis) might. What happens is: (A) a genetic mutation (usually associated with proliferation) (B) another genetic mutation (associated with proliferation, cell attachment, a protein regulating the epigenetic status etc.) (C) Epigenetic instability or change (induced by another mutation or by the environment-mechanical, transcription factor induced or cytokine/growth factor induced). However, some mutations are very strongly proliferative/oncogenic that an epigenetic change is seldom required during the cancer initiation.

The events can be in any direction- ABC, CBA, CAB. Each of these has clinical examples, although there could be significant overlap. Esophagial cancer (some forms) is an example of CAB. Persistent acid reflux from the stomach (GERD) will induce the esophagial epithelium to undergo metaplasia. A transdifferentiation to columnar cells. May be columnar cells are more resistant to acid reflux or it is a futile attempt of our body to resist acidity. However, the transdifferentiation requires an epigenetic change from the stratified squamous epithelium epigenome to columnar cell epigenome which involves activation or repression of several transcription factors. This weakens the stability of epigenomic landscape (which is unique to each cell type). At this point, if an oncogenic mutation occurs, in any of these dysplastic cells it may lead to cancer. But it is possible that an oncogenic mutation pre-exists in these cells and the "loose" epigenetic atmosphere now helped the oncogene to express taking over the normal cell cycle which is followed by another mutation which helped the cells to invade (ACB). Now at this point which cell one would call a cancer stem cell? Probably, it is possible that the very cell which initiated the cancer may not express even a single cancer stem cell marker! These stem cell markers may come and go at a later stage and they are dictated by the tumor environment. In short, cancer stem cell markers are the need of the time because, at some point of cancer evolution they help cancer cells to adapt and survive. In short cancer cells, which are not cancer stem cells can give rise to a cancer stem cells and cancer stem cells can give rise to cancer cells which are not qualified to be called cancer stem cells. Therefore, to conclude, cells which have a "loose" epigenetic status (on a background of one or more 'oncogene' mutations) are the ideal candidates for cancer "stem" cells. It is an epigenetically dynamic state. It is epigenetic 'anarchy' and 'promiscuity' for survival as a cancer cell.

On 2015 Jan 24, Madhusudana Girija Sanal commented:

How cancer stem cells may originate-the three hit hypothesis-the importance of epigenetic hit!

There are thousands (if not millions) of dangerous cancer associated mutations in every "healthy" human being. However, only a few get cancer. First of all one mutation may not lead to cancer, but two or more hits (the classic two hit hypothesis) might. What happens is: (A) a genetic mutation (usually associated with proliferation) (B) another genetic mutation (associated with proliferation, cell attachment, a protein regulating the epigenetic status etc.) (C) Epigenetic instability or change (induced by another mutation or by the environment-mechanical, transcription factor induced or cytokine/growth factor induced). However, some mutations are very strongly proliferative/oncogenic that an epigenetic change is seldom required during the cancer initiation.

The events can be in any direction- ABC, CBA, CAB. Each of these has clinical examples, although there could be significant overlap. Esophagial cancer (some forms) is an example of CAB. Persistent acid reflux from the stomach (GERD) will induce the esophagial epithelium to undergo metaplasia. A transdifferentiation to columnar cells. May be columnar cells are more resistant to acid reflux or it is a futile attempt of our body to resist acidity. However, the transdifferentiation requires an epigenetic change from the stratified squamous epithelium epigenome to columnar cell epigenome which involves activation or repression of several transcription factors. This weakens the stability of epigenomic landscape (which is unique to each cell type). At this point, if an oncogenic mutation occurs, in any of these dysplastic cells it may lead to cancer. But it is possible that an oncogenic mutation pre-exists in these cells and the "loose" epigenetic atmosphere now helped the oncogene to express taking over the normal cell cycle which is followed by another mutation which helped the cells to invade (ACB). Now at this point which cell one would call a cancer stem cell? Probably, it is possible that the very cell which initiated the cancer may not express even a single cancer stem cell marker! These stem cell markers may come and go at a later stage and they are dictated by the tumor environment. In short, cancer stem cell markers are the need of the time because, at some point of cancer evolution they help cancer cells to adapt and survive. In short cancer cells, which are not cancer stem cells can give rise to a cancer stem cells and cancer stem cells can give rise to cancer cells which are not qualified to be called cancer stem cells. Therefore, to conclude, cells which have a "loose" epigenetic status (on a background of one or more 'oncogene' mutations) are the ideal candidates for cancer "stem" cells. It is an epigenetically dynamic state. It is epigenetic 'anarchy' and 'promiscuity' for survival as a cancer cell.