I have written the following blog post and pinned it so that cancer researchers who may come across this blog post can get ideas about why cancer occurs, how to think about cellular states in tumor formation and how they relate to the driver mutations and the tumor microenvironment. Hope it is useful.
Cancer accelerates extended life span to death and therefore its frequency arises with age. The probabilities of errors in replication resulting in cancer causing mutation occur because of the second law of thermodynamics . Error in DNA replication implies lack of precision/accuracy in replication and an increase in randomness. This is exactly what the second law of thermodynamics predicts- an increase in entropy i.e randomness of the universe. With age the human dies, loss of physical organization of the human body occurs, matter gets converted to energy, and energy is returned back to the universe.
So for treatment of cancer local entropy has to be decreased to regain back organization/precision accuracy. This means drugs have to be discovered/designed /invented that decrease entropy/randomness/disorganization of the system in this case the malignant tumor.
Humans are only following the laws of physics. Elephants do not get cancer. They have multiple copies of the tumor suppressor p53. Their metabolism is slow resulting in large body size, and very long life spans. Lower metabolic rates means slower reactions and lower entropy. Humans unlike elephants have high rates of metabolism and accumulate toxic by-products. These contribute to errors in DNA replication which results in diseases such as cancer and the aging process.
Probably high metabolism rates is related to advanced cognitive capacities. Elephants may live longer , do not have cancer but they lack cognitive capacity comparable to humans . It is this cognitive capacity which has allowed humans to adapt themselves to the surroundings and influence their environment including climate. Maybe this advanced cognitive capacity will help design useful anti cancer drugs.
Tumor heterogeneity hypothesis-Different tumor cells possess altered ratios of tumor suppressing to tumor promoting activity, resulting in altered signaling networks in different cells.
Cancer occurs when there is impairement in restoration of homeostasis due to 2nd hit which is microenvironment related, in primary mutational hit (tumor suppressor inhibiting/oncogene activating) cells.
Sequence of events-Ist mutational hit. Cells starts dividing and at the same time retains homeostatic balance, so they form a benign tumor. Second hit occurs (tumor microenvironment interactions in which cells in the microenvironment lacking the mutation i.e. the soil fails to contain the dividing cells as they lack the primary mutation, and give insufficient inhibitory signals to the dividing cells) -Homeostasis breaks down, malignant Tumorigenesis results.
Cellular states preceding and following tumorigenesis are like- an oscillating pendulum that overshoots mean position once (equivalent to cellular state i.e benign tumor after primary mutational hit). The pendulum tries to come back to mean balance position (equivalent to restoring homeostasis in cell after primary mutational hit). Due to loss of elasticity of pendulum string (equivalent to secondary hit due to tumor microenvironment interactions) status quo of extreme position maintained, (which is equivalent to malignant tumor ).
Proposed Mechanism for the above:
What if the default mode of single cells is replication and differentiation/ maturation is secondary. Depending upon the interaction of replicating cells with the microenvironment, adjacent cells release inhibitory molecules which make a replicating cell differentiate/mature. This is because competition for food resources as a whole will wipe out cells, so for survival cells divide to a certain number and differentiate, so that the tissue survives as a whole.
In cancer the default replication of cells carrying driver mutations for tumorigenesis is not inhibited sufficiently by the surrounding cells so uncontrolled cell proliferation occurs. It is possible that driver mutations arise all the time in cells due to replication errors, but then such cells do not survive and proliferate because inhibitory signals by surrounding cells impedes their survival to allow tissue/organ/host formation to occur. This results in a benign tumor.
In malignant tumorigenesis the tumor survives at the expense of a host, because the cells in the neighbouring microenvironment of the cell carrying the driver mutation are not able to give out sufficient inhibitory signals to inhibit proliferation of cells carrying the driver mutation. One reason could be that a sufficient number of neighbouring cells lacking the driver mutation is needed to give out sufficient signals to inhibit proliferation of cells lacking the driver mutation. If cells lacking the driver mutation divide at a slower rate than cells with the driver mutation, then they will not be able to provide sufficient inhibitory signal against the cell carrying the driver mutation, resulting in a malignant tumor.
I found the following articles particularly useful: