Hallmarks of Cancer

Evading Growth Suppressors

 Along with growth stimulation, cancer cells need to overcome programs that negatively regulate cell
proliferation. These programs are mediated by tumor suppressor genes.
 
 Two of the most important tumor suppressors are RB ( retinoblastoma ) and TP53 proteins.

 In response to extracellular and intracellular signals, the RB protein decides if the cell divides or not.
On the other hand, TP53 responds to the level of DNA damage. If DNA is damaged, RB proteins halts
cell division until DNA repair occurs. However if the damage cannot be repaired, TP53 triggers
apoptosis.
 
 Loss just one these two regulator protein is not enough to escape the negative regulation of cell
proliferation, as great level of redundancy is observed in the fact that upon loss of one, the other
can efficiently regulate cell proliferation.
 Contact Inhibition

 Contact inhibition is mediated individually by the activity

of Merlin protein and epithelial polarity LKB1.

Taken from Mendonsa et al., 2018

 Inducing Angiogenesis

 Angiogenesis is induced by the activity of VEGF-A and

Inhibited by TSP-1.

 Components of the innate immune system are assemble at

tumor sites and promote formation of neovasculature.

Taken from Oliver and Waxman, 2019

 Activating Invasion and Metastasis

 Basically the process of invasion and metastasis

starts with local invasion, after which the cancer
cells undergo intravastion into nearly blood and
lymph vessels. The cancer cells transit through these
channels and then extravasate into distant tissues.
Here they form small nodules of cancer cells called
micrometastases which finally “colonize” to form
macroscopic tumors.
 This entire process basically comes under a regulatory program termed as “Epithelial-
mesenchymal transition” (EMT).

 The process of colonization by cancer cells is inverse of EMT and termed as mesenchymal-
epithelial transition (MET).
 Modes of Tumor Invasion

 Other than mesenchymal, two other forms of invasion

namely, collective and amoeboid form occur.

 In collective invasion, involves nodules of cancer cells

moving into adjacent tissue. Such cancers are rarely
metastatic

 On the other hand in case of amoeboid invasion,

individual cancer cells move through the interstices in
extracellular matrix.

Taken from Wu et al., 2021

 Tumor promoting inflammation

 Tumor tissue are greatly infiltrated by immune cells.

 These immune cells can provide factors that sustain proliferation, survival , metastasis etc for the
progression of cancer. They also provide ROS which accelerates the acquisition of new mutations
by cancer cells.
 Reprogramming energy metabolism

 Otto Warburg observed that even in presence of

oxygen, cancer cells reprogram their metabolism
to preferentially do glycolysis. This is termed as
“aerobic glycolysis”.

 The preference towards glycolysis is promoted

by hypoxic conditions that exist within tumors.
The hypoxia response system uprergulates
glucose transporters and enzymes of glycolysis.

 In case of some cancers two populations exist in

which the hypoxic cancer cells undergo aerobic
glycolysis while the other well oxygenated cells
use lactate as fuel.
 
 Evading Immune Destruction
 Evidence from literature points that increased tumor growth in response to carcinogen was observed in
immunodeficent mice relative to immunocompetent controls. This was more prevalent upon the loss of
cytotoxic T lymphocytes (CTLs) , T helper cells and natural killer cells (NK cells).

 Further more, it was observed that cancer cells from immunodeficient mice were unable to form secondary
tumors upon transplantation into immunocompetent controls. However, cancer cells from immunocompetent
mice were able to form secondary tumors upon transplantation into immunodeficent mice. This observation
gave rise to the concept of immunoediting.

 According to immunoediting, the immune system eliminates highly immunogenic cancer cells, leaving only
low immunogenic type cells to grow to form solid tumors.

 This gives rise to the possibility that cancer cells may develop means to overcome detection by immune
system. This may be achieved by secreting TGF-β to suppress the activity of NK cells and CTLs.