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.

45 related topics with Alpha

Overall
A coronal CT scan showing a malignant mesothelioma Legend: → tumor ←, ✱ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver

Cancer

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Group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.

Group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.

A coronal CT scan showing a malignant mesothelioma Legend: → tumor ←, ✱ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver
Symptoms of cancer metastasis depend on the location of the tumor.
The GHS Hazard pictogram for carcinogenic substances
Share of cancer deaths attributed to tobacco in 2016.
The incidence of lung cancer is highly correlated with smoking.
Cancers 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
Chest X-ray showing lung cancer in the left lung
Three measures of global cancer mortality from 1990 to 2017
Engraving with two views of a Dutch woman who had a tumor removed from her neck in 1689
University of Florida Cancer Hospital
CancerTreeMammal
An invasive ductal carcinoma of the breast (pale area at the center) surrounded by spikes of whitish scar tissue and yellow fatty tissue
An invasive colorectal carcinoma (top center) in a colectomy specimen
A squamous-cell carcinoma (the whitish tumor) near the bronchi in a lung specimen
A large invasive ductal carcinoma in a mastectomy specimen

Several studies have indicated that the enzyme sirtuin 6 is selectively inactivated during oncogenesis in a variety of tumor types by inducing glycolysis.

DNA damage resulting in multiple broken chromosomes

DNA repair

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Collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

Collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

DNA damage resulting in multiple broken chromosomes
Structure of the base-excision repair enzyme uracil-DNA glycosylase excising a hydrolytically-produced uracil residue from DNA. The uracil residue is shown in yellow.
Double-strand break repair pathway models
DNA ligase, shown above repairing chromosomal damage, is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide ester bond between the phosphate backbone and the deoxyribose nucleotides.
DNA repair rate is an important determinant of cell pathology
Most life span influencing genes affect the rate of DNA damage
A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error-prone microhomology-mediated end joining pathway with increased expression in various cancers.

Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.

The cell cycle. Many tumor suppressors work to regulate the cycle at specific checkpoints in order to prevent damaged cells from replicating.

Tumor suppressor gene

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Gene that regulates a cell during cell division and replication.

Gene that regulates a cell during cell division and replication.

The cell cycle. Many tumor suppressors work to regulate the cycle at specific checkpoints in order to prevent damaged cells from replicating.
Models of tumor suppression
Illustration of two-hit hypothesis

The suppression of tumorigenicity in these hybrid cells prompted researchers to hypothesize that genes within the normal somatic cell had inhibitory actions to stop tumor growth.

Illustration showing hematogenous metastasis

Metastasis

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Pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor.

Pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor.

Illustration showing hematogenous metastasis
Cut surface of a liver showing multiple paler metastatic nodules originating from pancreatic cancer
Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin
Main sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".
Pulmonary metastases shown on Chest X-Ray
Cut surface of a humerus sawn lengthwise, showing a large cancerous metastasis (the whitish tumor between the head and the shaft of the bone)
Micrograph of thyroid cancer (papillary thyroid carcinoma) in a lymph node of the neck. H&E stain
CT image of multiple liver metastases
CT image of a lung metastasis
Metastasis proven by liver biopsy (tumor (adenocarcinoma)—lower two-thirds of image). H&E stain.
Metastatic cancer in the lungs
Metastases from the lungs to the brain
Metastases from the lungs to the pancreas

This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis.

Figure 1: Stem cell specific and conventional cancer therapies

Cancer stem cell

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Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample.

Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample.

Figure 1: Stem cell specific and conventional cancer therapies
Figure 2: A normal cellular hierarchy comprising stem cells at the apex, which generate common and more restricted progenitor cells and ultimately the mature cell types that constitute particular tissues.
Figure 3. In the cancer stem cell (CSC) model, only the CSCs have the ability to generate a tumor, based on their self-renewal properties and proliferative potential.
Figure 4: In the clonal evolution model, all undifferentiated cells have similar possibility to change into a tumorigenic cell.
Figure 5: Both tumor models may play a role in the maintenance of a tumor. Initially, tumor growth is assured with a specific CSC (CSC1). With tumor progression, another CSC (CSC 2) may arise due to the clonal selection. The development of a new more aggressive CSC may result from the acquisition of an additional mutation or epigenetic modification.
Figure 6: Hierarchical organisation of a tumour according to the CSC model
Figure 7: The concept of migrating cancer stem cells (MSC). Stationary cancer stem cells are embedded in early carcinomas and these cells are detectable in the differentiated central area of a tumor. The important step toward malignancy is the induction of epithelial mesenchymal transition (EMT) in the stationary cancer stem cells (SCS), which become mobile or migrating cancer stem cells. Stem cells divide asymmetrically. One daughter cell will begin proliferation and differentiation. The remaining MCS migrates a short distance before undergoing a new asymmetric division, or disseminates through blood vessels or lymphatic vessels and produces a metastasis.

CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells.

Malignant transformation

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Process by which cells acquire the properties of cancer.

Process by which cells acquire the properties of cancer.

There are many causes of primary malignant transformation, or tumorigenesis.

Cigarettes have been known carcinogens for at least 65 years.

Carcinogen

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Cigarettes have been known carcinogens for at least 65 years.

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer.

Genome instability

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Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage.

Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage.

During the process of tumorogenesis, it is known that diploid cells acquire mutations in genes responsible for maintaining genome integrity (caretaker genes), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes).

A red tulip exhibiting a partially yellow petal due to a mutation in its genes

Mutation

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Alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA.

Alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA.

A red tulip exhibiting a partially yellow petal due to a mutation in its genes
Mutation with double bloom in the Langheck Nature Reserve near Nittel, Germany
Prodryas persephone, a Late Eocene butterfly
A covalent adduct between the metabolite of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA
Five types of chromosomal mutations
Selection of disease-causing mutations, in a standard table of the genetic code of amino acids
The structure of a eukaryotic protein-coding gene. A mutation in the protein coding region (red) can result in a change in the amino acid sequence. Mutations in other areas of the gene can have diverse effects. Changes within regulatory sequences (yellow and blue) can effect transcriptional and translational regulation of gene expression.
The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.
A mutation has caused this moss rose plant to produce flowers of different colors. This is a somatic mutation that may also be passed on in the germline.
Dutch botanist Hugo de Vries making a painting of an evening primrose, the plant which had apparently produced new forms by large mutations in his experiments, by Thérèse Schwartze, 1918

Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).

Epigenetic mechanisms

Epigenetics

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Study of heritable phenotype changes that do not involve alterations in the DNA sequence.

Study of heritable phenotype changes that do not involve alterations in the DNA sequence.

Epigenetic mechanisms
DNA associates with histone proteins to form chromatin.
Escherichia coli bacteria
Some acetylations and some methylations of lysines (symbol K) are activation signals for transcription when present on a nucleosome, as shown in the top figure. Some methylations on lysines or arginine (R) are repression signals for transcription when present on a nucleosome, as shown in the bottom figure. Nucleosomes consist of four pairs of histone proteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized tail (only one tail of each pair is shown). DNA is wrapped around the histone core proteins in chromatin. The lysines (K) are designated with a number showing their position as, for instance (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein. Methylations [Me], and acetylations [Ac] are common post-translational modifications on the lysines of the histone tails.

Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, DNA methylation reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.