Cancer

Cancer

Cancer is an uncontrolled, unrelenting proliferative cell disease that is linked to a number of additional complications. Cancer cells, malignant cells, or tumor cells are all names for this aberrant proliferative cell. Cancer cells do not reside at their original location; instead, they infiltrate and metastasize to other organs throughout the body, causing morbidity and mortality in people. Cancer is a major public health issue that ranks second in the world behind heart disease as the primary cause of death. Cancer metastasis is responsible for around 90% of all deaths among cancer patients. Cancer can affect almost any human tissue or organ, however, the likelihood of it happening differs depending on the tissue or organ.  The primary sites of cancer in humans are the tongue, mouth, pharynx, esophagus, stomach, small intestine, colon, rectum, anus, liver, intrahepatic bile duct, gallbladder, pancreas, larynx, lungs, bronchus, heart, skin, uterus, ovary, prostate, testis, urinary bladder, kidney, brain, thyroid, lymph, blood and also other unspecified sites (Siegel et al., 2019). Lung cancer is the most prevalent cancer in terms of both death and occurrence, and breast cancer is the second most frequent disease (Ferlay et al., 2015). Cancer rates in some tissues are millions of times higher than in others, and these disparities are related to lifelong risk factors in different tissues. (Tomasetti and Vogelstein, 2015).

Risk Factors of Cancer

Cancer is a complex disease with a wide range of risk factors. Non-modified intrinsic risk factors and non-intrinsic risk factors, which include partially modified internal variables and modified external environmental risk factors, are the most prevalent cancer risk factors. Common errors during the replication process are an intrinsic risk factor that is found in all species, is spontaneous in nature, and remains consistent in a population throughout time. Endogenous risk factors such as hormones, growth factors, inflammation, biological aging, DNA repair machinery, and genetic susceptibility, and exogenous risk factors such as chemical carcinogens, radiation, viruses, smoking, nutrient imbalance, lack of exercise, and other unhealthy lifestyles are examples of non-intrinsic risk factors (Wu et al., 2018).  Although the intrinsic risk factor remains constant in humans, the non-intrinsic risk factor plays a significant influence on cancer development. The occurrence of various forms of cancer in different populations is attributable to differences in non-intrinsic variables. (Collaboration, 2015; Zhu et al., 2017). Both risk factors working together increase the onset and progression of cancer. Cancer prevention begins with knowledge of cancer risk factors and their management.

Hallmarks of cancer

The transformation of a normal cell to a tumor cell is a multi-step process, and the tumor cell acquired the unique physiology required for tumor growth and maintenance during the onset and development of cancer. These acquired survival properties are known as the hallmarks of cancer (Moses et al., 2018). Cancer cells are aberrant cells that do not obey the normal control of cell physiology, according to several pieces of evidence. The characteristics obtained by cancer cells aid in the resistance to normal functional regulatory machinery and adapt cancer cells to successfully develop in a constrained environment. Genomic instability and mutation, immortality, tumor-promoting inflammation, evasion of growth suppression, ability to sustain proliferative signaling, resistance to cell death, activation of invasion and metastasis, induction of angiogenesis, evasion of immune destruction, and metabolic reprogramming are some of these common characteristics (Hanahan and Weinberg, 2011)

Genetic Basis of Cancer

The study of cancer's basic and fundamental causes aids in cancer prevention, diagnosis, and treatment. Cancer is a complex disease, and all of these causes changed the genes of the changing cell, causing cancer to initiate and progress. Advances in molecular technology and bioinformatic techniques aid in the detection of genetic changes in human cancer cells. Missense and nonsense mutations, insertions, deletions, duplications, translocation, frameshift mutation, and repeat expansion are all involved in carcinogenesis. Cancer is caused by a synonymous mutation in cancer genes that causes changes in RNA splicing, mRNA structure, and protein expression, as well as the initiation of cancer (Sharma et al., 2019). These changes in the cell are not all implicated in tumor progression; nevertheless, certain mutations cause tumor formation and are positively selected, which is known as a driving mutation. Some mutations do not help in tumorigenesis but originate during the expansion of cells known as passenger mutation. In addition to these mutations, epigenetic changes also have a great impact on tumor initiation and development (Rivenbark, 2017). Approximately 1 % of the total human functional genes have an immense role in cancer progression and are known as cancer genes. Approximately 90% of cancer genes undergo somatic mutation, 20% show germline mutation, and 10% have both types of mutation. Translocation mutations are the most common type of mutation in cancer genes (Futreal et al., 2004). The amount of mutations in cancer cells varies and is multifactorial, as it varies by age, with younger patients having fewer mutations than older patients, tumors in adult patients have a low number of mutations as compared to pediatric tumors. A lung cancer patient with a smoking history has a greater number of mutations than a non-smoker patient. For initiation of cancer minimum of 2-8 mutations are required, but it varies among the person and types of cancer (Vogelstein et al., 2013). The two most studied and common types of genes that regulate the development of cancer are known as oncogenes and tumor suppressor genes. Genetic alterations in these two genes cause the initiation, development, and progression of cancer.

Oncogene

Oncogenes (proto-oncogenes) are normally functioning wild-type genes that play a role in cellular proliferation or differentiation. The activation of these proto-oncogenes through chromosomal translocation, gene amplification, or point mutation alters normal cellular proliferation and differentiation, leading to cancer initiation and progression. Gain-in function mutations occur when a mutation in one allele of an oncogene triggers the growth of tumors. The structure of proto-oncogenes is altered by genetic modifications in oncogenes for activation, resulting in an abnormal oncogene product with abnormal function. Also results in the regulation of upregulated expression of normal growth-promoting proteins such as BCR-ABL translocation and point mutation in C-RAS and amplification of the c-Myc gene (Rivenbark, 2017). On the basis of the functions of proto-oncogenes protein products, oncogenes are generally classified into five different groups which are as follows.

• Growth Factor
• Growth Factor Receptor
• Signal Transducer 
• Transcription Factors and
• Other, such as programmed cell death regulators

Normal cell birth and death are regulated by these protooncogene products. The normal physiology of cell proliferation and differentiation is disrupted when these oncogene products are altered. Amplification of growth factors stimulated signaling cascades accelerated the cell proliferation and deregulation of protooncogene transcription factors further amplify the normal cell proliferation and decontrol the other physiological function that inhibits apoptosis of highly proliferative cells and susceptible cell turns benign (Pierotti, 2016).

Oncogene	Neoplasm	Mechanism of activation	Protein Function
Growth Factors V-SIS INT2 KS3 HST	Glioma/Sarcoma Mammary Carcinoma Kaposi Sarcoma Stomach carcinoma	Constitutive production Constitutive production Constitutive production Constitutive production	β – chain PDGF Member of FGF Family Member of FGF Family Member of FGF Family
GF Receptor Tyrosine Kinase Integral membrane proteins EGFR v-FMS v-Kit     TRK	Squamous cell carcinoma Sarcoma Sarcoma/GIST Colon/Thyroid carcinoma	Gene Amplification/ Point mutation Constitutive activation Constitutive activation/ Point Mutation DNA Rearrangement/fusion proteins	EGF-Receptor   CSF1 Receptor Stem cell Factor Receptor NGF Receptor
Signal Transducer Cytoplasmic Tyrosine kinase SRC v-YES v-FGR v-FES ABL	Colon carcinoma Sarcoma Sarcoma Sarcoma CML	Constitutive Activation Constitutive Activation Constitutive Activation Constitutive Activation DNA Rearrangement	Protein Tyrosine kinase Protein Tyrosine kinase Protein Tyrosine kinase Protein Tyrosine kinase Protein Tyrosine kinase
Membrane G-proteins HRAS   KRAS     NRAS   BRAF   GSP GIP   GTP exchange factor	Colon, Pancreas, lung carcinoma AML, melanoma, colon, lung, thyroid carcinoma Carcinoma, melanoma Melanoma, colon, thyroid, ovary Thyroid adenoma Ovary, Adrenal carcinoma Diffuse B-cell lymphoma, Hematopoietic cell	Point mutation   Point mutation     Point mutation   Point mutation   Point mutation Point mutation   DNA Rearrangement	GTPase   GTPase     GTPase   Ser/Thr kinase   Gs alpha Gi alpha   GEF for Rho & Ras
Serine/threonine kinase cytoplasmic v-VOS v-RAF PIM-1	Sarcoma Sarcoma T cell lymphoma	Constitutive activation Constitutive activation Constitutive activation	Ser/Thr kinase Ser/Thr kinase Ser/Thr kinase
Cytoplasmic Regulators	_	Constitutive tyrosine phosphorylation of cellular substrates	SH-2/SH-3 adaptor
Transcription Factors v-MYC   N-MYC L-MYC v-MYB v-FOS v-JUN v-SIO v-ETS-1 v-ETS-2 v-ERB A1 v-ERB A2	Carcinoma myelocytomatosis Neuroblastoma Lung carcinoma Myeloblasts Osteosarcoma Sarcoma Carcinoma Erythroblastosis Erythroblastosis Erythroblastosis Erythroblastosis	Deregulated activity   DNA amplification Deregulated activity Deregulated activity Deregulated activity Deregulated activity Deregulated activity Deregulated activity Deregulated activity Deregulated activity Deregulated activity	Transcription factor   Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor Transcription factor
Others BCL2 MDM2	B-cell lymphoma Sarcoma	Constitutive activity Gene amplification	Antiapoptotic protein Complex with P53

Tumour Suppressor Gene

Tumor suppressor genes work in the opposite direction of oncogenes, inhibiting cell proliferation and inducing apoptosis. Cell proliferation and benign development are initiated and progressed by genetic and epigenetic alterations in these genes. The loss of function mutation is caused by the inactivation of the tumor suppressor gene and haploinsufficiency prevents cells from performing their usual functions, which can lead to cancer. Gatekeeper genes, also known as caretaker genes, are tumor suppressor genes. PTEN, P53, P27, NF1, APC, and RB1 are gatekeeper genes involved in cell proliferation, differentiation, and apoptosis, whereas ATM, ATR, BARC1, BARC2, and DNA mismatch repair genes are caretaker genes engaged in overcoming genetic instability. A mutation in the gatekeeper gene causes cancer to start by disrupting cellular proliferation and apoptosis, but a mutation in the caretaker gene causes genomic instability, which leads to more mutations in the gatekeeper gene and other genes. Landscapers are the third group, in which a mutation in this gene causes improper stromal cell proliferation, resulting in an abnormal tissue microenvironment, and epithelial cells linked with such proliferating cells become neoplasms, as in juvenile polyposis syndrome. (Macleod, 2000). Many genes' transcription and signal transduction pathways are regulated by tumor suppressor gene products. Tumour suppressor gene-mediated carcinogenesis has a variety of mechanisms that are still being studied. These gene products receive, gather, and send inhibitory signals from the environment to the cell. When any component of this inhibitory cascade is missing, the cell loses its link to external growth inhibitory signals, leading to benign tumor development. Furthermore, tumor suppressor genes govern cell-cell and cell-matrix interactions; mutations in these genes result in altered cellular shape, lack of physiological intracellular connection, and signaling, all of which are hallmarks of neoplastic cells.

Genetic alteration and oncogenic signaling

Signaling pathways are responsible for cells' physiological behaviors, which include receiving commands from anywhere and acting on them. Information from distant extracellular and neighboring microenvironments is relayed to intracellular and then to all responsive cell organelles via this signaling pathway. Cellular signaling networks communicate with one another and instruct the cell to behave accordingly.  Cellular signaling pathways control the physiological activities of cells such as proliferation, growth, differentiation, metabolism, motility, survival, and death. An abnormality in the cellular signaling cascades causes the cell to function abnormally. Hyper and hypoactivation of signaling pathways, which can be induced by genetic or epigenetic processes, cause dysregulation of cellular signaling. This can result in a wide range of disorders, including cancer. It is widely recognized that the disruption of normal cellular regulation by various signaling pathways contributes to cancer (Vogelstein, 2004). Several signaling pathways have been linked to genetic changes in oncogene and tumor suppressor gene products. It has long been known that cancer-causing mutations disrupt cellular signaling, allowing oncogenic signaling to flourish. (Sever, 2015). Mutations in proto-oncogenes resulted in oncogenes that overexpressed or created mutant proteins with unregulated activity, which were responsible for signaling pathways that are frequently activated in numerous physiological responses such as growth factor receptors tyrosine kinase (EGFR), small GTPase (RAS), serine/threonine kinase (AKT), cytoplasmic tyrosine kinase (Src & Abl), lipid kinase (PI3K) and also in developmental signaling pathways such as Wnt, Hedgehog (Hh), Hippo and Noth (Skoda, 2018)(Hirate, 2014). Other tumor suppressor genes that have been inactivated have been unable to regulate the activating signaling pathways that cause carcinogenesis. The most commonly mutated gene in cancer is p53, also known as the guardian of the genome, which is required for cell proliferation as well as other stress responses like DNA damage response and apoptosis. Mutations in retinoblastoma protein, CKIs such as p16, p21, p27, and other genes are unable to stop the cell cycle from progressing. Many tumor suppressor genes are oncogenic signaling negative regulators, such as the adenomatous polyposis-coli protein (APC) and PTEN, which are negative regulators of the Wnt and PI3K-AKT pathways, respectively (Sever, 2015). The cancer genome atlas (TCGA) has identified signaling pathway genetic changes in 33 different cancer types. The extent, mechanism, and changes in these signaling pathways vary depending on the type of tumor. Melanoma, colorectal cancer, Her-2 enriched breast cancer, pancreatic cancer, IDH1-wild type glioma, lung adenocarcinoma, and thyroid carcinoma were found to have the most often changed RTK-RAS pathway across all cancer types. Melanoma, thymoma, testicular cancer, and acute myeloid leukemia all have altered cell cycle pathways. The WNT pathway was altered in many tumors and ubiquitous in colorectal cancer, and the AKT pathway was observed in non-hypermutated uterine cancer and esophagogastric cancer. Some signaling pathways are mutually exclusive, whereas others occur simultaneously. These pathways are interdependent, and changing one activates the other without requiring other changes. (Sanchez-Vega, 2019).

References

Carbone, A. (2020). Cancer classification at the crossroads. Cancers, 12(4), 980.

Collaboration, G.B.o.D.C. (2015). The global burden of cancer 2013. JAMA oncology 1(4), 505.

Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., et al. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer 136(5), E359-E386.

Futreal, P.A., Coin, L., Marshall, M., Down, T., Hubbard, T., Wooster, R., et al. (2004). A census of human cancer genes. Nature reviews cancer 4(3), 177-183.

Hirate, Y., & Sasaki, H. (2014). The role of angiomotin phosphorylation in the Hippo pathway during preimplantation mouse development. Tissue barriers, 2(1), 1181-94.

Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. cell 144(5), 646-674.

Moses, C., Garcia-Bloj, B., Harvey, A.R., and Blancafort, P. (2018). Hallmarks of cancer: the CRISPR generation. European Journal of Cancer 93, 10-18.

Rivenbark, A.G. (2017). "An Overview of Cancer Genes," in The Molecular Basis of Human Cancer. Springer), 121-142.

Sanchez-Vega, F., Mina, M., & Marra, M. A. (2019). Pathways, Oncogenic Signaling Cancer, The Atlas, Genome. Cell, 173, 321-337.

Sharma, Y., Miladi, M., Dukare, S., Boulay, K., Caudron-Herger, M., Groß, M., et al. (2019). A pan-cancer analysis of synonymous mutations. Nature communications 10(1), 1-14.

Siegel, R.L., Miller, K.D., and Jemal, A. (2019). Cancer statistics, 2019. CA: a cancer journal for clinicians 69(1), 7-34.

Sever, R., & Brugge, J. S. (2015). Signal transduction in cancer. Cold Spring Harbor perspectives in medicine, 5(4), a006098.

Skoda, A. M., Simovic, D., Karin, V., Kardum, V., Vranic, S., & Serman, L. (2018). The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosnian journal of basic medical sciences, 18(1), 8.

Tomasetti, C., and Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347(6217), 78-81.

Vogelstein, B., & Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nature medicine, 10(8), 789-799.

Vogelstein, B., Papadopoulos, N., Velculescu, V.E., Zhou, S., Diaz, L.A., and Kinzler, K.W. (2013). Cancer genome landscapes. science 339(6127), 1546-1558.

Wu, S., Zhu, W., Thompson, P., and Hannun, Y.A. (2018). Evaluating intrinsic and non-intrinsic cancer risk factors. Nature communications 9(1), 1-12.

Zhu, W., Wu, S., and Hannun, Y.A. (2017). Contributions of the Intrinsic Mutation Process to Cancer Mutation and Risk Burdens. EBioMedicine 24, 5-6.