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Popławski Tomasz Cancer Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions 2 3  An abnormal mass of tissue that forms when cells...

Popławski Tomasz Cancer Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions 2 3  An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should.  Neoplasms may be benign (not cancer) or malignant (cancer).  Benign neoplasms may grow large but do not spread into, or invade, nearby tissues or other parts of the body.  Malignant neoplasms can spread into, or invade, nearby tissues.  They can also spread to other parts of the body through the blood and lymph systems. 4 5 6 7  to elucidate the biochemical and genetic mechanisms that underlie the uncontrolled growth of cancer cells,  to elucidate cancer cells ability to invade and metastasize  to develop successful treatments that destroy cancer cells, while causing minimal damage to normal cells 8 https://doi.org/10.1186%2F1749-8546-5-37 9  Acquired mutations ▪ exposure to environmental carcinogens  Inherited mutations ▪ hereditary. ▪ number of familial conditions that predispose to hereditary cancer  Spontaneous mutations ▪ occur at a frequency of approximately 10 −7 to 10 −6 per cell per generation.  Oxidative stress 10 11 12 13  Direct carcinogens can interact with DNA without prior enzyme activation. Indirect carcinogens are activated by an enzyme (eg, a cytochrome P450 species) to the ultimate carcinogen and then interact with DNA 14 Initiation is the stage where exposure to a chemical causes irreversible DNA damage. Promotion comprises the stage at which an initiated cell begins to grow and proliferate abnormally. The cumulative effect of these stages is a neoplasm. 16 Integration of viral DNA with the host DNA results in various events such as deregulation of the cell cycle, inhibition of apoptosis, and abnormalities of cell signaling pathways. 17  Oncogenes encode various proteins that can drive the growth of cancer cells. Oncogenes are derived from proto-oncogenes. Tumor suppressor genes encode proteins that normally suppress cell growth, but which are inactivated when altered by mutations. 18 a Gene amplification may be recognized as homogeneously stained regions on chromosomes, or as double minute chromosomes 19 20 (1) Normal chicken chromosome showing an inactive MYC gene. (2) An avian leukemia virus has integrated in the chromosome in its proviral form adjacent to the MYC gene. Its right-hand long terminal repeat (LTR), containing a strong promoter, lies just upstream of the MYC gene and activates that gene, resulting in transcription of MYC mRNA. For simplicity, only one strand of DNA is depicted and other details have been omitted. Enhancer insertion acts similarly, except that the site of inte- gration may be downstream or considerably upstream, and it cannot act as a promoter. Instead, a specific proviral sequence acts as an enhancer element, leading to activation of the MYC gene and its transcription 21 The chromosomes involved are 8 and 14. A segment from the end of the q arm of chromosome 8 breaks off and moves to chromosome 14. The reverse process moves a small segment from the q arm of chromosome 14 to chromosome 8. The MYC gene is contained in the small piece of chromosome 8 that was transferred to chromosome 14; it is thus placed next to genes transcribing the heavy chains of immunoglobulin molecules, and itself becomes activated. Many other translocations have been identified, with perhaps the best known being that involved in formation of the Philadelphia chromosome 22 Examples of ways by which oncoproteins work 23 Shown are examples of various proteins encoded by oncogenes (oncoproteins) 24 https://dx.doi.org/10.1016%2Fj.chom.2014.02.011 25 26 27 https://www.youtube.com/watch?v=HORqbHYksQo 28 29 30 31 http://dx.doi.org/10.2217/fon.13.259 32 33  The various genes listed are either oncogenes, tumor suppressor genes or genes whose products are closely associated with the products of these two types of genes. The cumulative effects of mutations in the genes listed are to drive colonic epithelial cells to proliferate and eventually become cancerous. They achieve this mainly via effects on various signaling pathways affecting cellular proliferation. Other genes and proteins not listed here are also involved. 34  Cancer is truly a genetic disease, but in a somewhat different sense from the normal meaning of the phrase, insofar as many of the gene alterations are due to somatic mutations.  Carcinogenesis is a multistep process - a minimum of five to six genes must be mutated for cancer to occur.  Additional subsequent mutations are thought to confer selective advantages on clones of cells  Many of the genes implicated in colorectal carcinogenesis and other types of cancers are involved in cell signaling events. 35  Many other growth factors have been identified.  Growth factors may be made by a variety of cells, or may have mainly one source.  Many different interleukins have now been isolated; along with the interferons and some other proteins/polypeptides, they are referred to as cytokines 36 http://www.bioscience.org/2002/v7/d/pinzani/figures.htm 37  Reduce tobacco use  Date from Stein CJ,  Increase physical activity Colditz GA: Modifiable  Control weight risk factors for cancer.  Improve diet Brit J Cancer  Limit alcohol 2004;90:299  Use safer sex practices  Routine cancer screening tests  Avoid excess exposure to the sun 38 39   Rb and Rb-p represent the unphosphorylated and the phosphorylated forms of the retinoblastoma protein.  In G0 and early G1, Rb physically associates with E2F factors and blocks their transactivation domain.  In late G1, Rb-p releases E2F, allowing the expression of genes that encode products necessary for S-phase progression. Oncogene (2006) 25, 5220–5227 40   p53 is activated by a range of cellular stress signals.  These activators of p53 include nutrient stress, hypoxic conditions, activation of oncogenes, DNA damage, and oxidative stress from reactive oxygen species (ROS).  Canonical responses of p53 include, transcriptionally and translationally, cell cycle arrest and repair DNA damage.  Non-canonical, controlled programmed cell death roles include autophagy pathways, necrosis, necroptosis, and ferroptosis. http://dx.doi.org/10.3390/cancers10060189 41 42 https://doi.org/10.3390/diagnostics11030544 43 44 45 46 47  Condition Gene Major Function Major Clinical Feature Development of many early-onset adenomatous Adenomatous polyposis of the APC DNA repair polyps, which are immediate precursors of colon (OMIM 175100) colorectal cancers About 5% of women in N America with breast Breast cancer, early onset (OMIM BRCA1 DNA repair cancer carry mutations in this gene or in BRCA2. 113705) Also substantially increases risk of ovarian cancer As stated above for BRCA1. Mutations in this gene Breast cancer, early onset (OMIM BRCA2 DNA repair also increase the risk of ovarian cancer, but to a 600185) lesser extent Hereditary nonpolyposis cancer, MSH2 DNA mismatch repair Early onset of colorectal cancers type I (OMIM 120435) Li-Fraumeni syndrome (OMIM A rare syndrome involving cancers at different sites, P53 DNA repair 151623) developing at an early age Neurofibromatosis, type 1 (OMIM Varies from a few cafe au lait spots to development NF1 Encodes neurofibromin 162200) of thousands of neurofibromas Retinoblastoma (MIM 180200) RB1 DNA repair Hereditary or sporadic retinoblastoma 48 49 50 51  Necrosis of tissue results in release of intracellular contents into its surrounding microenvironment.  It result in the infiltration of tissue by immune inflammatory cells.  Immune inflammatory cells promote angiogenesis, cell proliferation and invasiveness.  Inflammatory cells that supply the tumor cells with growth-promoting factors. Necrosis, may benefit tumorigenesis! 52  (A) Methylation of cytosine to form 5′methylcytosine. The cytosine is usually located next to a guanine residue, forming a CpG island.  Methylation of cytosine by a methyltransferase is associated with silencing of the activities of certain genes.  (B) Posttranslational modifications of various histones. Specific residues in specific histones are modified by various enzymes, changing the conformations and activities of the modified histones. 53 54 55 56  Cadherins  Immunoglobulin (Ig) superfamily (Ig CAMs; cell adhesion molecules)  Integrins  Selectins CAMs may be homophilic or heterophilic. Homophilic CAMs interact with identical molecules on neighboring cells, whereas heterophilic CAMs interact with different molecules. Cadherins are homophilic, selectins and integrins are heterophilic, and Ig CAMs may be either. 57  An epithelial-to-mesenchymal cell transition is often found in cancers, allowing increased movement of potentially metastatic cells.  Metastasis is relatively inefficient (only about 1:10,000 tumor cells may have the genetic potential to colonize).  Metastatic cells must evade various cells of the immune system to survive.  Changes in cell surface molecules (eg, CAMs and others) are involved.  Increased proteinase activity (eg, of MP-2 and MP-9) facilitates invasion.  The existence of metastasis enhancer and suppressor genes has been shown.  Some cancer cells metastasize preferentially to specific organs.  Metastasis gene signatures may be detected by transcriptome/exome analysis; such transcriptome information can be of prognostic value, potentially allowing for personalized therapeutic treatment. 58 Changes in metabolism have now been reproducibly observed in most cancer cells. Metabolic protein-encoding genes (and related genes) are commonly mutated in the 21 different common tumor types. https://doi.org/10.3390/ijms22126173 60 61  Tumor Biomarker Associated Cancer Alpha-fetoprotein (AFP) Hepatocellular carcinoma, germ cell tumor Calcitonin (CT) Thyroid (medullary carcinoma) Carcinoembryonic antigen (CEA)Colon, lung, breast, pancreas, ovary Human chorionic gonadotropin Trophoblastic disease, germ cell (hCG) tumor Monoclonal immunoglobulin Myeloma Prostate-specific antigen (PSA) Prostate Most of these tumor biomarkers are also elevated in the blood of patients with noncancerous diseases. For example, CEA is elevated in a variety of noncancerous gastrointestinal disorders, and PSA is elevated in prostatitis and benign prostatic hyperplasia. This is why interpretation of elevated results of tumor markers must be made with caution and why their main uses are to follow effectiveness of treatments and to detect recurrences. A number of other quite widely used tumor biomarkers are also available. 62 63 64