DIFFERENTIATION AND THE CURE.
5TH LAW OF NATURE

Although it would have been nice if there were clear cut cross-road between DIFFERENTIATION and PROLIFERATION.  Nature has understood that most tissues will need to be repaired particularly when it comes to the skin.  Therefore some differentiated cells could trigger de-defferentiation when repair is needed.  The question is then how could the shift occur.  What makes a hyperdifferentaiated cell shift gears and enter proliferation.
Stimuli from outside the cells including local specific growth factors (TGF Beta, nerve growth factor,Epidermal growth factor, Epiregulin, transforming Growth factor, Platelet derived GF,  and so on) attach to its cellular receptor, and trigger N,H,C, K -RAS.  and depending on the type of RAS, differentiation will be directed.  There are other point of tissue specificity but the family of RAS is one area of folk differentiation.

One other location of folk differentiation is at the level of transcription genes and at genetic  plicing  (PRPF8,
U2AF2 (keep an eye on this one),  WT-1 (looks like EGFR), PUF60, ASF/SF2,WDR,EFTUD2, PPFIA-down regulates androgen for differentiation, SF3B1 etc...

Researchers looking at NRAS and KRAS function were manipulating a Colon cancer cell when the find themself with a cell with putative stem cell features indicating that whatever stimuli being applied reversed the cell to open up totipotential characteristic.  We know that cell from skin would repair wound through proliferative process.  Increase in TNF and Interferons would yield fibrotic tissue.  After a trauma,These growth factors will direct efforts to another type of RAS.  The RAS stimulation follow the MEK transduction signal to lead to appropriate transcription and splicing factors for relevant nuclear events globally!

The thing is the more  complete the differentiation, the less the proliferative potential.

This beg a question that investigators have been struggling, forcing full differentiation by maximizing differentiation a viable strategy for cure by silencing proliferation.   One thing is for sure, high dose interferon disrupts growth factor effects and had been for a while the only treatment for Melanoma until BRAF was interfered with and now regulation of the MEK/MAP kinase has also been inhibited.  Disruption of growth factors at the membrane leads to expression of molecules and disruption of Glycocalyx susceptible to recruit
immune cells. 

THIS SAME MECHANISM would more likely lead to cirrhosis in the liver where injury lead to  change of growth factors leading to preponderance of fibrous tissue and new nodules.  This is differentiation challenged by "trauma" to the liver tissue!