Lecture 16: Biology of Cancer

Question 1

cancer

Answer 1

disease that occurs when cell division is out of control or dysregulated cell growth happens

Question 2

neoplasia

Answer 2

• the process by which abnormal tissue or cells grow uncontrollably in the body
• the abnormal growth itself is called a neoplasm or tumor

Question 3

is cancer on the rise?

Answer 3

• yes, 17% increase in new cases since 2013, 5.1% increase in deaths/yr. since 2013, and 5.1% increase in deaths/day since 2013
• however, almost 3 million male deaths and 1 million female deaths have been averted from anti-smoking campaigns

Question 4

is cancer a genetic disease or a mitochondrial metabolic disease according to the somatic mutation theory? does cancer arise from nuclear somatic mutations or from chronic mitochondrial damage with compensatory fermentation?

Answer 4

current dogma: supported by confirmation bias, the somatic mutation theory of cancer states that cancer is a genetic disease, in which cancer cells carry the oncogenic and tumor suppressor mutations in the nucleus making it a genetic disease.”

Question 5

somatic mutation theory

Answer 5

suggests that cancer is a genetic disease involving nuclear mutations in oncogenes and tumor suppressor genes that inhibit or stimulate cell division

Question 6

behaviors of a normal tumor-suppressor gene

Answer 6

normal tumor-suppressor gene > normal growth-inhibiting protein > cell division under control > normal cell growth. a tumor-suppressor gene normally codes for a protein that inhibits cell growth and division. in this way, the gene helps prevent cancerous tumors from arising

Question 7

behaviors of a mutated tumor-suppressor gene

Answer 7

mutated tumor-suppressor gene > detective, nonfunctioning protein > cell division not under control > uncontrolled cell growth (cancer). when a mutation in a tumor-suppressor gene makes its protein defective, cells that are usually under the control of the normal protein may divide excessively, forming a tumor

Question 8

how a proto-oncogene can become an oncogene

Answer 8

how a proto-oncogene (a normal gene that helps regulate cell division) can turn into an oncogene (a gene that promotes uncontrolled cell growth, leading to cancer):

mutation within the gene:
* a mutation occurs in the DNA of the proto-oncogene itself
* causes the production of a hyperactive or abnormal growth-stimulating protein
* result: excessive and uncontrolled cell division

multiple copies of the gene:
* proto-oncogene is duplicated, creating extra copies of itself
* causes an overproduction of normal growth-stimulating proteins
* result: unregulated cell division, even though the protein is not mutated

gene moved to a new DNA position:
* proto-oncogene is relocated within the genome, possibly near a different promoter
* new promoter causes the gene to be overexpressed, producing an excessive amount of normal growth-stimulating protein
* result: uncontrolled cell division

Question 9

proto-oncogene

Answer 9

a healthy gene that helps cells grow and divide normally

Question 10

oncogene

Answer 10

a mutated proto-oncogene that can cause cancer by causing cells to grow and divide uncontrollably

Question 11

how many mutations does a cell accumulate in order to go from a normal cell to a malignant cancer cell?

Answer 11

normal cell (normal chromosomes) > 1 mutation > 2 mutations > 3 mutations > malignant cell (4 mutations)

Question 12

when this happens to Driver genes, they cause cancer

Answer 12

• a sequential series of alterations in well-defined Driver genes
• normal cell (normal chromosomes) > 1 mutation > 2 mutations > 3 mutations > malignant cell (4 mutations)

Question 13

Driver genes

Answer 13

genes that contain mutations that are causally linked to cancer progression

Question 14

are new cancer drugs working or not?

Answer 14

new cancer drugs aren’t working
* data available at the time of FDA drug approval indicated that novel cancer therapies between 2000-2016 were associated with substantial tumor responses but with a median overall survival increase by only 2.4 months

Question 15

evidence challenging the somatic mutation theory of cancer

Answer 15

ideological dogma and confirmation bias prevent rational thinking

Question 16

the complicated origins of the somatic mutation theory of cancer (SMT)

Answer 16

• the SMT and the view that cancer is a genetic disease originated with Theodore Boveri’s speculative essay on the origin of malignant tumors that was published in 1914
• Boveri had no prior research experience with cancer and based his views on the origin of tumors from observing abnormal cell division in sea urchins

Question 17

challenges to the somatic mutation theory

Answer 17

• Apologetic Ignorance of Cancer (Boveri)
• Absence of Gene Mutations in Some Cancer Cells (Parsons, Baker, Greenman)
• Cancer “Driver” Genes Found in Normal Cells (Martincorena, Yokoyama, Yizhak)
• Some Carcinogens Do Not Cause Mutations (Soto and Sonnenschein)
• Rarity of Cancer in Aboriginal Tribes (Berglas)
• Rarity of Cancer in Chimpanzees (Varki and Varki)
• Off Target Effects of Precision Cancer Drugs (Fojo)
• The Nuclear Mitochondrial Transfer Experiments (Seyfried)

Question 18

findings of tadpole cloned from nucleus of frog renal cell tumor and their relationship w/ the SMT

Answer 18

• even though the nucleus came from a cancer cell, it directed the formation of a fully developed, normal-looking tadpole when placed in a healthy cytoplasmic environment
• findings are inconsistent with the somatic theory of cancer

Question 19

mouse embryos cloned from brain tumors

Answer 19

“although medulloblastoma-derived embryos died, none exhibited uncontrolled proliferation resembling tumorigenesis” > these findings are inconsistent with the somatic mutation theory of cancer

Question 20

reprogramming of a melanoma genome by nuclear transplantation

Answer 20

the presence of trisomy 8 and trisomy 11 in embryonic mice cloned from a tumor cell nucleus provides unequivocal genomic evidence that the R545-1 NT ES cell was cloned from a tumorigenic nucleus of the R545 tumor cell line > findings are inconsistent with the somatic mutation theory of cancer

Question 21

cancer as a mitochondrial metabolic disease, according to Prof. Seyfried

Answer 21

Prof. Seyfried’s paper abstract:
“cancer is widely considered a genetic disease involving nuclear mutations in oncogenes and tumor suppressor genes. this view persists despite the numerous inconsistencies associated with the somatic mutation theory. in contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg. the findings are reviewed from nuclear cytoplasm transfer experiments that relate to the origin of cancer. the evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease”

Question 22

role of the nucleus and mitochondria in the origin of tumors and their relationship to SMT inconsistencies

Answer 22

the following fndings are inconsistent with the nuclear somatic mutation theory of cancer:
* normal cell > regulated growth
* tumor cell > dysregulated growth
* normal cytoplasm + tumor nucleus > regulated growth
* tumor cytoplasm + normal nucleus > dysregulated growth

Question 23

the ideological dogma of the somatic mutation theory

Answer 23

the continued acceptance of the SMT as an explanation for the origin of cancer must be based more on ideological dogma than on rational thought

Question 24

mitochondrial metabolic theory of cancer: who created it and what it it?

Answer 24

created by Otto Warburg in a 1956 paper titled On the Origin of Cancer Cells
* cancer arises from damage to cellular respiration
* energy through fermentation gradually compensates for insufficient respiration
* cancer cells continue to ferment lactate in the presence of oxygen (Warburg Effect)
* the “missing link”: cancer cells continue to ferment glutamine in the presence of oxygen (Q-Effect)
* enhanced fermentation is the signature metabolic malady of all cancer cells

Question 25

energy metabolism in cancer cells (slide 55)

Answer 25

Glycolysis (in the cytosol):
cancer cells heavily rely on glycolysis to generate energy, even in the presence of oxygen (Warburg Effect). this produces lactic acid and accounts for 20% of the ATP through substrate-level phosphorylation (direct ATP production from glycolysis).

Krebs Cycle (in the mitochondria):
the Krebs cycle (or citric acid cycle) produces intermediates like succinic acid, generating more ATP through substrate-level phosphorylation. this contributes to 75% of the ATP, showing that some mitochondrial metabolism is still functional in cancer cells

Electron Transport Chain (ETC):
in normal cells, the ETC in the mitochondria is responsible for most ATP production via oxidative phosphorylation. but in cancer cells, ETC activity is inefficient (as noted earlier, due to defects in mitochondrial lipids like cardiolipin). this leads to only 5% of ATP being produced through oxidative phosphorylation.

What This Means:
* substrate-level phosphorylation dominates: cancer cells produce most of their ATP via substrate-level phosphorylation in glycolysis and the Krebs cycle, rather than oxidative phosphorylation
* energy inefficiency: cancer cells are less energy-efficient, relying on processes that yield less ATP per glucose molecule. this necessitates increased glucose consumption to meet their energy needs

this metabolic shift allows cancer cells to survive in hypoxia and supports their rapid growth, but it also means they depend heavily on glucose for energy

Question 26

what are the major fermentable fuels for all cancers

Answer 26

glucose (energy source) and glutamine (TCA cycle support)

Question 27

glucose-driven glycolysis and glutamine-driven glutaminolysis synergize to do what

Answer 27

drive dysregulated cancer cell growth