
<b>Carcinogenesis, Accumulation of More Mutations, and De-Differentiation

How Cancer Starts [Carcinogenesis]</b>
Mutations occur to the genes of cells by exposure to 'ionizing' radiation [like the sun's rays, radioactivity, Xrays], or chemical mutagens [like benzene and its derivatives] or viruses [which can introduce foreign DNA into the cell's DNA] or autoantibodies to DNA [created if a person has an autoimmune disease.]

The usual mutation is one that causes a gene NOT to work. This means that the enzyme/protein that the gene produces [the gene product] does NOT work. 
For cancer to happen, a single cell needs to accumulate five or six different mutations. The usual probability of this happening is very very small.

<b>So what makes it happen?</b>
In every healthy normal cell, during reproduction there is a safety mechanism that checks that the DNA is intact and has no errors.  The p53 gene is part of this safety mechanism.  If the DNA is damaged, and cannot be repaired, then the p53 gene sets off a series of reactions that leads to apoptosis---the cell self-destructs.  The p53 gene is called "the guardian of the genome" because it does not allow faulty DNA to exist, or to be passed on in the cell line.  The "guardian of the genome" will cause a cascade of reactions that lead to apoptosis in cells whose DNA is damaged and cannot be repaired. What happens if the "the guardian of the genome" has a mutation? 

<b>If the Guardian Gene Doesn't Work</b>
So a key mutation in the development of cancer would be damage to this p53 gene, or damage somewhere in its cascade of reactions.  If the p53 cascade of reactions does not occur, then faulty DNA CAN is passed on from the mother to the daughter cell.  Furthermore, the cell line with faulty p53 can now start collecting mutations.   If the "caretaker gene" doesn't work, it allows defective-DNA daughter cells in the next generation. The defective daughter cells then accumulate their own additional mutations, which are ALSO passed to THEIR daughters. Who also accumulate some additional mutations. Which are ALSO passed to THEIR daughters. And so on...
 
Eventually, besides not being able to police its own DNA, there will be mutations involving reproduction and growth, invasiveness, and coherence to other cells.  When you have a cell that cannot destroy faulty DNA, which has ungovernable growth, which invades neighboring tissue, and which can separate itself from other tissue and journey via lymph or bloodstream to grow in a new place, you have an invasive, metastasizing cancer.  

So 'loss of function' mutations in these "caretaker genes" lead to an accumulation of mutations in the cell, and these mutations are carried through to subsequent cell generations. These cells are genetically unstable, as more and more mutations accumulate, and ARE PASSED ON to the next generation of cells. Inexorably, and inevitably, eventually, a cancerous cell will occur.  

<b>Accumulation of More Mutations</b>
In the cells with defective p53, as more mutations occur, they are passed on to the daughter cells, and the daughter cells pass the mutations on to their daughters, along with further new mutations which have occurred.  The results of these actions means that the tumor made up of these cells is not homogeneous...it is not composed of the same cancer cell repeated again and again.  It actually is composed of many different branches of cell lines, with an increasing numbers of mutations.  There will different mutations from one batch of cancer cells to another.  It is this variation in the cell lines, in their mutations, that can make it difficult to interpret and apply chemosensitivity/resistance testing.  The tumor may be sensitive to a chemotherapy agent in one of its cell lines, but resistant in another.  Or one metastasis can be sensitive, and another resistant.

<b>Dedifferentiation</b>
Differentiation is the process by which the original fertilized egg, and its descendants, change from being identical to each other to being different...e.g. hair follicle cells and muscle cells and nerve cells and blood cells.... and so on.  Differentiation refers to the process by which the cells become different from each other as they become more sophisticated, specialized types of cells.  
As the cancer cells in the tumor accumulate more and more mutations, the specialized nature of the original cell is lost.  For instance, if it originally had an estrogen receptor on its cell membrane, often that receptor is lost.  The cell with more and more mutations loses its abilities because of those mutations, and becomes less specialized and more primitive.  And as more and more damage accumulates, the cell becomes more and more primitive, aberrant, and bizarre.  This process is called dedifferentiation.  It occurs in all cancers, it is inevitable, and it is a function of time, as it takes time to accumulate the mutations.  It will usually occur more quickly in tumors with high reproductive rates, and can be hastened by chemotherapy or radiation.  It may result in tumors that suddenly grow uncontrollably - even while being treated with chemotherapy AND radiation.  
