Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include – enhanced ability to divide without terminally differentiating, induce new blood vessel formation, overcome contact inhibition to form a large mass of cells, escape apoptosis, and invade and colonize other tissues. Cancer cells also have increased tolerance to mutations and altered metabolism for rapid energy production.
Cellular senescence generally depends on the progressive shortening of the ends of chromosomes called telomeres. Cells produce a reverse transcriptase enzyme called telomerase that prevents the telomere shortening during successive cell division cycles. However, after a certain number of cell divisions, telomerase enzymes' expression decreases, pushing the cell towards apoptosis. Cancer cells overcome this selection pressure by overexpressing the telomerase enzyme, allowing cells to continue the cell division and delay cellular senescence.
Rapidly growing tumors must be accompanied by rapid vasculature to provide oxygen and nutrients to all the tumor cells. Due to the diffusion limit of oxygen, the inner core of a large tumor is deficient in oxygen and, therefore, has a hypoxic environment. At the same time, the outer layer of cells that is enriched with blood vessels continues to proliferate. The inner core cells slowly start losing viability due to the lack of oxygen, creating a gradient of cell viability across the tumor mass. Interestingly, the hypoxic cells show higher resistance to radio and chemo-therapy due to reduced reactive oxygen species production and altered metabolism.
Also, hypoxic conditions induce the expression of hypoxia-inducible factors (HIF), which modulate the expression of a broad range of genes involved in angiogenesis, cell survival and death, metabolism, cell-cell adhesion, extracellular matrix remodeling, migration, and metastasis.
