Somatic evolution of malignancy

Teleological

Senior Member
Joined
Nov 6, 2007
Messages
836
#1
Cancer cell phenotypes are characterized by the manifestation of six essential alterations in cell signaling pathways and are usually associated with upregulation of glycolysis, resulting in increased glucose consumption.
Cell signaling alterations include: [1]
1) self-sufficiency in growth signals
2) insensitivity to growth-inhibitory signals
3) evasion of programmed cell death (apoptosis and autophagy)
4) limitless replicative potential
5) sustained angiogenesis
6) tissue invasion and metastasis

Carcinogenesis is a multistep process and is often described as occurring by somatic evolution. According to this model, molecular properties that contribute to cancer cell fitness are retained and selective pressures remove weak fitness traits. Therefore traits that are unique to cancer cells are thought to arise as adaptive mechanisms to environmental proliferative constraints during carcinogenesis. As listed above, cancer phenotypes have cell signaling and metabolic alterations and these two alterations are interdependent, meaning metabolic pressures can alter cell signaling and visa versa. However, the curious observation that the vast majority (if not all) of malignant cancer phenotypes exhibit an increase in glycolysis (Warburg effect), whether in aerobic or anaerobic conditions, suggests a potential therapeutic window. Why is aerobic glycolysis a recurring property of malignant tissues?

Somatic evolution [2]
Stage 1: Neoplastic growth

Cell growth in normal tissue is tightly controlled by pro-growth cell signaling and cell death signaling (apoptosis and autophagy). During the life of normal healthy cells, mutations may occur whereby crucial regulatory mechanisms are altered, resulting in increased, uninhibited proliferation and abrogated cell death signaling of normal cells, with the end result being neoplastic growth. A few examples:
a) p53. p53 (deregulated in +-50% of cancers) is the guardian of the genome and is involved in DNA damage checkpoint signaling, cell cycle regulation and apoptosis. Abrogated p53 signaling usually results in insensitivity to DNA damage, resulting in the increased growth, decreased apoptosis and allowing more mutations to occur.
b) Deregulated protein tyrosine kinase and phosphatase signaling resulting in increased pro-growth signaling.
c) Transforming growth factor beta (TGFb) deregulation, resulting in the production of vascular endothelial growth factor (VEGF). VEGF is a potent inducer of angiogenesis.
d) Deregulation of other tumor suppressor proteins e.g. PTEN, BRCA1 and 2, retinomablastoma protein (pRB), c-myc (deregulation is common in cancers, possibly plays a role as a tumor promoter and suppressor, depending on the mileu) etc.
The end result of the deregulation of cell signaling events associated with proliferation is neoplastic growth.

Stage 2: Pre-malignant growth

Neoplastic growth increases because of changes (caused by mutations) resulting in self-sufficiency in growth signals, insensitivity to growth-inhibitory signals and evasion of programmed cell death (apoptosis and autophagy). Increased neoplasia causes cells to grow further away from their basement membrane. As a result, substrates such as oxygen and nutrients (glucose) must travel further to reach these neoplastic cells. The diffusion distance of oxygen from the basement membrane of capillaries is limited, therefore as neoplastic cells grow further away from oxygen supplies, the environment becomes hypoxic. It is at this stage of neoplastic growth where selection forces will favor phenotypes that adapt to this hypoxic environment. How can cells adapt to a hypoxic environment?

Stage 3: Malignant growth
Enter hypoxia inducible factor (HIF-1alpha): the likely culprit.
Under normal oxygen (normoxic) level conditions, HIF-1alpha is rapidly degraded after synthesis by the ubiquitin-26S proteosome pathway. When oxygen levels (tension) are low (hypoxic) HIF-1alpha is stabilized and translocated into the nucleus to activate transcription of a wide array of genes that are critical for adaptation to low oxygen levels. Most importantly, glycolytic gene expression is increased, resulting in increased glycolysis.

Genes include:
Genes involved with angiogenesis: VEGF
Glycolytic enzymes: glucose transporter (GLUT) 1 and 3, hexokinase (HK) 1 and 2, glucosephosphate isomerase (GPI), phosphofructokinase (PFK), aldolase (ALD) and C, triosephosphate isomerase (TPI), glyceraldephosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) 1, enolase (ENO) 1, pyruvate kinase (PK) M,
Transcription factors: AP-1, CREB, GATA-1, and GATA-2
Other: c-myc, TGFb, p53

HIF-1alpha also induces the expression of two proteins that are able to restrict oxidative phosphorylation (OXPHOS) (This is of course useful under hypoxic conditions).
a) Lactate dehydrogenase (LDH) A: Needed for the production of NADH to be used in glycolysis.
b) Pyruvate dehydrogenase kinase (PDK) 1: Inhibits pyruvate dehydrogenase activity, reducing the amount of acetyl-CoA substrate needed for OXPHOS.

Therefore, under selective pressure induced by hypoxia, fundamental changes in cell metabolism of pre-malignant cells occurs leading to increased glycolysis. However, increased glycolysis under hypoxic conditions leads to an increased formation of lactic acid causing the environment to become acidic. The acidic environment leads to the further selection of cells that are capable of tolerating the acidic environment. Cells surviving all these ordeals (mutations, hypoxia, acidosis) are nightmares for cancer patients and doctors. Not only do they evade cell death and growth inhibitory signals, and survive hypoxic conditions, they use up all the energy of surrounding tissues because glycolysis does not produce as much energy as OXPHOS and finally they release copious amounts of lactic acid.

Stage 4: Emergence of the metastatic phenotype
Lactic acid released by malignant cells is able to breakdown the surrounding tissue, allowing the cells to enter capillaries. From there the malignant cells can be transported to many parts of the body, implanting into tissue and continue merrily to grow without restriction. Finally, if these cells are not kept under wraps, they will use all the energy from surrounding tissue and lactic acid will cause irreparable damage., finally resulting in system shutdown and death. Another one to chalk up to the “powers of evolution”.

How can this information be used to treat cancer? Well glycolysis is a very inefficient way of attaining energy from glucose. Glycolysis only produces 2 ATP molecules from one molecule of glucose, while OXPHOS can theoretically produce up to 36 ATP molecules from on glucose molecule. This suggests a potential therapeutic window. Yet remarkably, no drug exists on the market that selectively targets this vulnerability.

A few molecules are however doing the rounds in the research community.

2-Deoxyglucose (pre-clinical)
3-Bromopyruvate (Pre-clinical, similar in structure to DCA)
Lonidamine (various phases of clinical trials for various cancers)
Dichloroacetate (DCA) (Phase 3 clinical trial)
Glufosfamide

Two molecules stand out as promising future agents. More on their mechanism of action later…

For a few pics, have a look here

References:
1) Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.
2) Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004 Nov;4(11):891-9.
 
Last edited:

cerebus

Honorary Master
Joined
Nov 5, 2007
Messages
34,862
#2
Could you write a little summary paragraph to let us know what you're getting at with this?
 

Teleological

Senior Member
Joined
Nov 6, 2007
Messages
836
#3
Could you write a little summary paragraph to let us know what you're getting at with this?
Ill try:

Cancer is the multi-stage progression whereby normal cells are changed in such a way that they gain advantage over other cells to proliferate in an uncontrolled way, normally to the disadvantage of the host. Along the way, cancer cells undergo fundamental changes in their biochemistry. These changes can then be used to target as weak points and are a potential avenue for research into compounds that specifically target these weak points. Research have been trying to find a golden bullet to selectively kill only cancer cells for a long time, however with limited success.

The above post was to give background information on carcinogenesis, and then give examples of exciting and upcoming research into compounds that specifically target the bioenergetic weak points of cancer cells and how these compounds are able to do it.
 
Last edited:

cerebus

Honorary Master
Joined
Nov 5, 2007
Messages
34,862
#7
Oh. Well I'd love to join in this because it sounds fascinating but it's waaay over my head. :)
 

Teleological

Senior Member
Joined
Nov 6, 2007
Messages
836
#8
Possible mechanism of cell death dichloroacetic acid (DCA):
The short version:
Cancer cells are like old dysfunctional minis and beetles (dangerous and probably dysfunctional), while normal cells are like well-made German sports-cars custom-made to handle NOS.

DCA straps a nitrous oxide (incidentally also a ROS species) container to the engine of cancer cells and it goes… well don’t do it to an old beetle if you plan to use it in future.
 
Top