A report on Carcinogenesis

Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.
The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis
Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.
Tissue can be organized in a continuous spectrum from normal to cancer.
Many tumor suppressor genes effect signal transduction pathways that regulate apoptosis, also known as "programmed cell death".
Multiple mutations in cancer cells

Formation of a cancer, whereby normal cells are transformed into cancer cells.

- Carcinogenesis
Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

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Two-hit hypothesis

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Hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change.

Hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change.

It was later found that carcinogenesis (the development of cancer) depended both on the mutation of proto-oncogenes (genes that stimulate cell proliferation) and on the inactivation of tumor suppressor genes, which are genes that keep proliferation in check.

Location and appearance of two example colorectal tumors

Colorectal cancer

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Development of cancer from the colon or rectum (parts of the large intestine).

Development of cancer from the colon or rectum (parts of the large intestine).

Location and appearance of two example colorectal tumors
Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.
Colon cancer with extensive metastases to the liver
Relative incidence of various histopathological types of colorectal cancer. The vast majority of colorectal cancers are adenocarcinomas.
Micrograph of colorectal adenocarcinoma, showing "dirty necrosis".
A diagram of a local resection of early stage colon cancer
A diagram of local surgery for rectal cancer
Colon and rectum cancer deaths per million persons in 2012

As summarized in the articles Carcinogenesis and Neoplasm, for sporadic cancers in general, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or silence expression of DNA repair genes.

Angiogenesis following vasculogenesis

Angiogenesis

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Physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis.

Physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis.

Angiogenesis following vasculogenesis
3D medical animation still showing angiogenesis
Without angiogenesis a tumor cannot grow beyond a limited size

Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity, inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis.

Endoscopic image of sigmoid colon of patient with familial adenomatous polyposis

Familial adenomatous polyposis

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Autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine.

Autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine.

Endoscopic image of sigmoid colon of patient with familial adenomatous polyposis
CHRPE - Congenital hypertrophy of the retinal pigment epithelium
Micrograph of a tubular adenoma, the colorectal cancer precursor most commonly associated with FAP
Colectomy specimen showing numerous polyps throughout the large bowel

(APC regulates β-catenin, a protein that plays a crucial role in cell communication, signalling, growth, and controlled destruction, but which left uncontrolled also gives rise to numerous cancers ).

Whereas hypertrophy stems from an increase in cell size, hyperplasia results from an increase in cell number.

Hyperplasia

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Enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation.

Enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation.

Whereas hypertrophy stems from an increase in cell size, hyperplasia results from an increase in cell number.
Patient with hemihyperplasia involving the upper and lower left extremities. The leg length discrepancy can be noted by the pelvic tilt.

This differs from neoplasia (the process underlying cancer and benign tumors), in which genetically abnormal cells manage to proliferate in a non-physiological manner which is unresponsive to normal stimuli.

Acrolein

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Simplest unsaturated aldehyde.

Simplest unsaturated aldehyde.

Acrolein is one of seven toxicants in cigarette smoke that are most associated with respiratory tract carcinogenesis.

Colonic epithelium from a mouse not undergoing colonic tumorigenesis (A), and a mouse that is undergoing colonic tumorigenesis (B). Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-oxo-dG. The level of 8-oxo-dG was graded in the nuclei of colonic crypt cells on a scale of 0-4. Mice not undergoing tumorigenesis had crypt 8-oxo-dG at levels 0 to 2 (panel A shows level 1) while mice progressing to colonic tumors had 8-oxo-dG in colonic crypts at levels 3 to 4 (panel B shows level 4) Tumorigenesis was induced by adding deoxycholate to the mouse diet to give a level of deoxycholate in the mouse colon similar to the level in the colon of humans on a high fat diet. The images were made from original photomicrographs.

8-Oxo-2'-deoxyguanosine

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Oxidized derivative of deoxyguanosine.

Oxidized derivative of deoxyguanosine.

Colonic epithelium from a mouse not undergoing colonic tumorigenesis (A), and a mouse that is undergoing colonic tumorigenesis (B). Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-oxo-dG. The level of 8-oxo-dG was graded in the nuclei of colonic crypt cells on a scale of 0-4. Mice not undergoing tumorigenesis had crypt 8-oxo-dG at levels 0 to 2 (panel A shows level 1) while mice progressing to colonic tumors had 8-oxo-dG in colonic crypts at levels 3 to 4 (panel B shows level 4) Tumorigenesis was induced by adding deoxycholate to the mouse diet to give a level of deoxycholate in the mouse colon similar to the level in the colon of humans on a high fat diet. The images were made from original photomicrographs.
Initiation of DNA demethylation at a CpG site. In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides (CpG sites), forming 5-methylcytosine-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 8-hydroxy-2'-deoxyguanosine (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits TET1 and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC.
Demethylation of 5-Methylcytosine (5mC) in neuron DNA. As reviewed in 2018, in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).

They also noted that increased levels of 8-oxo-dG are frequently found during carcinogenesis.

CT scan of a liver with cholangiocarcinoma

Liver cancer

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Cancer that starts in the liver.

Cancer that starts in the liver.

CT scan of a liver with cholangiocarcinoma
Liver tumor types by relative incidence in adults in the United States (liver cancers in dark red color).
This electron micrograph shows hepatitis B virus "Dane particles", or virions.
High magnification micrograph of a liver with cirrhosis. Trichrome stain. The most common cause of cirrhosis in the Western world is alcohol use disorder – the cause of cirrhosis in this case.
Left lobe liver tumor in a 50-year-old male, operated in King Saud Medical Complex, Riyadh, Saudi Arabia
A surgeon performing photodynamic therapy
Deaths from liver cancer per million persons in 2012

Mutation in p53, presumably in conjunction with other aflatoxin-induced mutations and epigenetic alterations, is likely a common cause of aflatoxin-induced carcinogenesis.

Acrylonitrile

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Organic compound with the formula CH2CHCN.

Organic compound with the formula CH2CHCN.

Acrylonitrile is one of seven toxicants in cigarette smoke that are most associated with respiratory tract carcinogenesis.

The ability to invade surrounding tissue and metastasise is a hallmark of cancer.

The Hallmarks of Cancer

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The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities.

The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities.

The ability to invade surrounding tissue and metastasise is a hallmark of cancer.
Signalling pathways are deregulated in cancer. Hanahan and Weinberg compared the signalling pathways to electronic circuits where transistors are replaced by proteins. The prototypical Ras pathway starts with an extracellular signal from growth factors (such as TGF-α). Other major extracellular signals are anti-growth factors (such as TGF-β), death factors (such as FASL), cytokines (such as IL-3/6)and survival factors (such as IGF1). Proteins inside the cell control the cell cycle, monitor for DNA damage and other abnormalities, and trigger cell suicide (apoptosis). Hanahan and Weinberg's signal pathway illustration is at Cell 100:59
The cell cycle clock. Cells do not divide in G0 and are quiescent. After receiving growth factor signals, they prepare for division by entering G1, where everything within the cell except DNA is doubled. This doubling includes the size of the cell. The next phase of the cell cycle is S (synthesis) phase. It is the cell cycle phase where the chromosomes (DNA) are duplicated in preparation for cellular division. The transition from G1 to S is a checkpoint. If the cell has damaged DNA or is expressing oncogenes or other inappropriate proteins, specialized checkpoint proteins, tumor suppressors such as p53 or pRB, will interrupt the transition to S phase until the damage is repaired. If the damage cannot be repaired, the cell will initiate apoptosis, often referred to as cellular suicide, which is programmed cell death. If the tumor suppressor genes incur loss-of-function mutations or are knocked out, the damaged cell can continue to divide unchecked – one of the hallmarks of cancer.
The hallmarks of cancer.

Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates.