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REVIEW ARTICLE
Year : 2015  |  Volume : 5  |  Issue : 1  |  Page : 1-6

The factors influencing carcinogenesis and its genetic and molecular basis


Department of Surgery, Late Shri Baliram Kashyap Memorial Government Medical College, Jagdalpur, Chhattisgarh, India

Date of Web Publication13-Mar-2015

Correspondence Address:
S N Agrawal
Main Road, P.O. Jagdalpur - 494 001, Bastar, Chhattisgarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-9596.153138

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  Abstract 

Cancer is a genetic disease and genetic mutation is in the heart of carcinogenesis. We attribute the defects to gene, but in fact it is their genetic protein products that regulate all cell activities, like cell division, deoxyribonucleic acid (DNA) repair, apoptosis, cell differentiation, etc. When they (gene and genetic protein) get mutated, a step ahead is taken towards carcinogenesis. The mutation leads to some basic attributes which ultimately is responsible for carcinogenesis. These are self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, unlimited replicative potential, sustained angiogenesis, invasive and metastasizing capabilities, and genomic instability due to defects in DNA repair. It is not necessary that all the attributes are essentially playing part at a given time, but some may be playing more important role than other. An endeavor is made in this article to address these attributes and their influence in carcinogenesis.

Keywords: Angiogenesis, apoptosis, carcinogenesis, DNA repair, genomic instability, oncogene


How to cite this article:
Agrawal S N. The factors influencing carcinogenesis and its genetic and molecular basis. Arch Int Surg 2015;5:1-6

How to cite this URL:
Agrawal S N. The factors influencing carcinogenesis and its genetic and molecular basis. Arch Int Surg [serial online] 2015 [cited 2021 May 12];5:1-6. Available from: https://www.archintsurg.org/text.asp?2015/5/1/1/153138


  Introduction Top


Multicellular organisms constantly multiply their cells for either growth or replacement of lost cells. This cellular proliferation takes place by cell division. One cell gives rise to two daughter cells. This is a continuous process throughout the life of organism, although different cell type divides differently.

In 1969, Dr. Leonard Hayflick made the observation that human umbilical cord fibroblast stopped dividing after 50 divisions in culture - a phenomenon came to be known as Hayflick's limit. Contributing to the Hayflick's limit is the irreversible shortening of the telomere, when after each cell division it becomes shorter and with too short telomere, the cell cannot further divide, [1] for a cell to generate two daughter cells complete copies of the entire cell constituents of nucleus and cytoplasm is to be made and genetic information is exactly copied to both the daughter cells.

The cell cycle is a highly regulated affair and establishes a balance between cell proliferation, cell differentiation, and cell death. As per requirement, cells may divide throughout their life, others may permanently leave active cell division after differentiation. Some cells may remain in a state of quiescence (G0, phase of cell cycle) and reenter cell cycle when required.

Cells are lost by death (of cell), sloughing, injury etc., and are replaced by cell division, a highly balanced phenomenon and is called homeostasis. If the normal cellular regulatory mechanisms malfunctions and gets unregulated, the unchecked cell division may result. This gives rise to condition known as cancer.

It is best to consider carcinogenesis in context of seven fundamental changes in cell physiology that together determine its malignant attribute:

  1. Self-sufficiency in growth signals.
  2. Insensitivity to growth inhibitory signals.
  3. Evasion of apoptosis.
  4. Unlimited replicative potential.
  5. Sustained angiogenesis.
  6. Invasive and metastasizing potentials.
  7. Genomic instability due to defects in deoxyribonucleic acid (DNA) repair.


Self-sufficiency in growth signals

Oncogenesis is a process by which a normal cell is transformed into cancer cell. This is caused by mutation and epimutation of genetic material of normal cells, which upsets the balance between proliferation and cell death. This causes uncontrolled cell division and formation of cancerous growth. More than one mutation is necessary for oncogenesis. In fact, a series of mutation to certain class of gene is usually required for a normal cell to transform into cancer cell. [2] Many changes which involve carcinogenesis are mutation, changes in nucleoside sequence, aneuploidy (presence of abnormal number of chromosomes), deletion or gain of a portion of chromosomes, genomic amplification, translocation (two separate chromosomal region become abnormally fused), etc. Small scale mutation includes point mutation, insertion mutation, deletion, etc. Epimutation include methylation or demethylation of genes, which results in repression or derepression of genetic expression.

Because of these mutagenic changes, cells acquire carcinogenic potential by achieving self-sufficiency in growth signals, that is, they do not require dependency on growth factor or other external signals. It is achieved by following mechanism.

Normal cells require stimulation, by growth factor, to undergo proliferation. Many cancer cells synthesize some growth factor themselves, to which they respond by proliferation (autocrine action). For example, glioblastoma secrete platelet-derived growth factor (PDGF) and express PDGF receptors.

Growth factor receptors: Mutant gene gives rise to mutant receptor proteins that deliver continuous mutagenic signals to cell, even in absence of relevant growth factor in environment. There may also be over expression of growth factor receptors that renders cancer cells responsive to levels of growth factor that would normally not trigger cell proliferation.

For example, amplification of HER-/neu receptors in breast carcinoma, over expression of epidermal growth factor (EGF) receptors in squamous cell carcinoma of lung. [3]

Signal transducing proteins: Mutated gene causes cell to achieve growth autonomy by encoding various components of signaling pathways of growth factor receptors. For example, RAS is most commonly mutated proto-oncogene. Approximately 20% of all tumors have activated mutation in one of the RAS gene. [4]

Tumor suppressor gene

Tumor suppressor genes code, that antiproliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressor genes are transcription factor that are activated by cellular stress or DNA damage. Tumor suppressor genes normally function to halt the cell cycle progression within G1 of cell cycle events.

It is important that nuclear synthesis of DNA does not begin until all the appropriate cellular growth has occurred during G1. These key regulators ensure that G1 is completed prior to start of S phase of cell cycle.

p53 gene is called guardian of genome. It is the most studied tumor suppressor gene and is a transcription factor. Loss of p53 function can contribute to genomic instability within cell.

Its unique functions are as follows.

Regulates the gene expression and controls several key genes involved in growth regulation.

Facilitates DNA repair. When DNA damage is encountered, p53 senses the damage, and causes G1 arrest of cell cycle, until the damage is repaired.

If the damage cannot be repaired, p53 triggers apoptosis of these cells. Over 50% of all human cancers show p53 mutations.

Retinoblastoma (RB) protein

This tumor suppressor protein functions to halt a cell in G1 phase of cell cycle. In resting cell, the RB protein contains free phosphorylated amino acid residue. In this state it prevents entry of cell cycle to S phase by binding to transcription factor E2F and its binding partner DP1/2 which is critical for the G1/S transcription. The RB gene was cloned in 1987 and was the first tumor suppressor gene cloned. The RB gene product, RB protein is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development.

Dr. Alfred Khudson proposed a theory known as Khudson's "two hit" hypothesis. According to this hypothesis, single mutation is not sufficient for tumorogenesis. He further hypothesized that hereditary RB involves two mutations, of which one is germ line and other is somatic, whereas the nonhereditary RB is due to two somatic mutations. [5]

As with RB protein, normal p53 also can be rendered nonfunctioning with certain DNA viruses. Protein encoded by oncogenic human papillomavirus (HPV), hepatitis B virus (HBV), and possibly Epstein-Barr virus (EBV) can bind to normal p53/RB and abolish its protective function.

Transferring growth factor (TBG-β) pathway

In most normal epithelial, endothelial, and hematopoietic cells; TBG-β is a potent inhibitor of proliferation. In many forms of cancer, the growth inhibitory effects of TBG-β pathways are impaired by mutation in the TBG-β signaling pathways. Mutations affecting the receptor are seen in cancers of the colon. In 100% of pancreatic cancers and 83% of colon cancer, at least one component of TBG-β pathway is mutated.

Avoidances of apoptosis

Apoptosis is a programmed cell death. It is fundamental to cellular and tissue physiology just like division and differentiation. Disturbance in pathways that regulates apoptosis may result in cancers, autoimmune disease, and neurodegenerative disorders.

Apoptosis is an important function for survival of organism. It eliminates the damaged cells which are beyond repair, or infected with virus, or under the influence of ionizing radiation, toxins, etc.

There are two distinct mechanisms that activate apoptosis. Extrinsic pathway: It is also called death receptor pathway. They initiate apoptosis in response to external stimuli. Those members who have this property possess a homologous cytoplasmic sequence called death domain (DD). Molecules like FAS-associated DD (FADD) and tumor necrosis factor α-receptor (TNFR)-associated DD (TRADD) contain such domain. They interact with death receptors to transmit the apoptotic signals to the death machinery via activation of caspase 8 or 10. [6]

Intrinsic pathway: Internal cell death program is initiated when there is irreparable damage to cellular components or its DNA. There is formation of apoptosome, which cleaves and destroys cellular protein and DNA which causes cell death by apoptosis. In the human cancers, aberration in the apoptotic program is predominantly seen.

Unlimited replicative potentials

A fundamental difference in the behavior of normal versus tumor cell is that normal cell divide for a limited number of times (Hayflick's limit). [1] Where as, tumor cells usually have the ability to proliferate indefinitely (they are immortal). It is now evident that progressive loss of the telomeric end of chromosome is an important limiting factor in cell division. Human telomere contains long stretches of repetitive sequence, TTAGGG which is bound by specific proteins. With each cell division, telomere shortens permanently because the lagging strand of DNA synthesis is unable to replicate the extreme-3 end of chromosome (known as the end replication problem). [7]

When telomere becomes sufficiently short, cell enters into an irreversible growth arrest called cellular senescence. In most instances cells become senescent before they can accumulate enough mutations to become cancerous. Thus, the growth arrest induced by short telomere may be a potent anticancer mechanism.

Telomerase, a eukaryotic ribonucleoprotein (RNP) complex helps to stabilize telomere length in human stem cells, reproductive cells, and cancer cells by adding TTAGGG repeats onto the telomere using its intrinsic ribonucleic acid (RNA) as a template for reverse transcription. Telomerase activity has been found in almost all human tumors, but not in adjacent normal cells. The most prominent hypothesis is that maintenance of telomere stability is required for the long-term proliferation of tumors. [8] The escape from the cellular senescence and becoming immortal by activating telomerase, or an alternative mechanism to maintain telomere, constitutes an additional step in oncogenesis, which most tumors require, for their ongoing proliferation.

This makes telomere a target not only for cancer diagnosis, but also for the development of anticancer therapeutic agents.

Most human cancers have short telomeres and express high levels of telomerase, whereas in most normal somatic tissues, telomerase is absent. [9]

Telomerase has been examined in hundreds of studies as a potentially sensitive biomarker for screening, early cancer detection, prognosis, or in monitoring as an indicator of residual disease.

Angiogenesis

Tumors cannot enlarge beyond 1-2 mm in diameter unless they are adequately vascularized. Like normal tissues, tumor cells require delivery of oxygen and nutrients and removal of waste products, and for that it is essential to have angiogenesis for the survival and growth of tumor.

When angiogenesis is stimulated; proangiogenic growth factors like vascular endothelial growth factor (VEGF), PDGF, and transforming growth factor (TGF) are released. [10] New blood vessel formation occurs as endothelial cells (ECs) use matrix metaloprotease (MMPs) and integrin to digest extracellular matrix (ECM) and migrate into new territory where they lengthen and form tubes.

The proliferation of new lymphatic vessels, that is, lymphangiogenesis is also thought to be controlled by VEGF family. Signaling in lymphatic cells is thought to be modulated by VEGFR3. Experimental studies with VEGF-C and VEGF-D have shown that they can induce tumor lymphangiogenesis and direct metastasis via the lymphatic vessels and lymph nodes. [11]

There are many angiogenesis inhibitors available for therapeutic use. They inhibit various steps in process of angiogenesis. For example, bevacizumab (Avastin® ) is a monoclonal antibody that specifically recognizes and binds to VEGF. [12] When VEGF is attached to bevacizumab, it is unable to activate the VEGF receptor. Other angiogenic inhibitors including sorafenib and sunitinib bind to receptors or surface of ECs or to other proteins in the downstream signaling pathways, blocking their activities.

US Food and Drug Administration (USFDA) has approved the use of bevacizumab in certain cases of glioblastoma and other cancers like colorectal cancers, some non-small cell lung cancers and metastatic renal cell cancers.

Invasive and metastasizing potentials

A feature of the malignant cell is their ability to invade normal surrounding tissue and to reach to distant organs (metastasis). Tumors in which malignant cells appear to lie within basement membrane are called in situ cancers. Tumors in which malignant cells are demonstrated to breach the basement membrane and penetrate surrounding tissue are called invasive cancers. Spread of tumors is a complex process and involves a series of sequential steps:

Step 1: Loosening of tumor cells.

Step 2: Local degradation of basement membrane and interstitial connective tissues.

Step 3: Attachment of new ECM components; during carcinogenesis the ECMmodifies in a way that promotes invasion and metastasis.

Step 4: Dissemination is the final step of migration; the tumor cells are passed through, degraded basement membrane and ECM.

Step 5: Metastasis; metastasis arises by the spread of cancer cells from primary site and the formation of new tumors at distant sites.

Genomic instability due to defects in DNA repair

The basic cause of carcinogenesis is genetic mutation. Protooncogene regulates and produces proteins that control normal cell growth and development. Mutations that alter protooncogene may convert them from regulatory gene into cancer causing oncogenes. The importance of DNA repair in maintaining the genome is highlighted by several inherited disorders in which the genes that encode proteins involved in DNA repair are defective. Individuals born with such inherited defects in DNA repair are at a greatly increased risk of developing cancer.

Some important such defects are as follows.

Defective mismatch repair: During DNA replication, DNA polymerase may introduce single nucleotide mismatch or small insertions or deletion loops. These errors are corrected through a process called mismatch repair.

When mismatch gene are inactivated, DNA mutation in other genes that are critical to cell growth and proliferation accumulate rapidly. In hereditary nonpolyposis colorectal cancer (HNPCC), germline mutation have been identified in several genes, that play a key role in DNA nucleotide mismatch repair, for example, human muts homologue-1 (hMLH-1), human muts homologue-2 (hMSH-2), hMSH-6, human post meiotic segregation-1(hPMS-1), and hPMS-2 of which hMLH-1 and hMLH-2 are most common. [13] One of the hallmarks of the patients with mismatch repair defect is microsatellite instability (MSI).

Defective nucleotide excision repair system

In patients with xeroderma pigmentosa, there is defect in DNA repair. These patients are at increased risk of developing cancer through exposure to ultraviolet (UV) lights. UV lights causes cross linking of pyrimidine residue and this prevents normal DNA replication.

Defective recombination repair

In women with early onset breast cancer nearly 10% have germline mutation in one of the BRCA-1 or BRCA-2.

BRCA-1 and BRCA-2 encode for large nuclear protein, 208 and 384 kDa, respectively, that has been implicated in process fundamental to all cells, including DNA repair and recombination, checkpoint control of cell cycle, and transcription. [14]

Other mutations like RB gene product. RB protein is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development. The oncogenesis may be due to point mutation, a chromosomal deletion, loss of heterozygosity or silencing of an existing gene.

Phosphatase and tensin homologue (PTEN) deleted on chromosome 10, deletion or mutation of this tumor suppressor gene is found in a number of carcinomas in breast, prostate, kidney, etc. It was identified as susceptibility gene for the autosomal dominant syndrome, Cowden disease (CD), or multiple hamartoma syndromes. [15]

P-16 gene mutilations are found in about 20% of melanoma prone families. E-Cadherin. It is a cell adhesion molecule that plays an important role in normal architecture and function of epithelial cells. Its mutation is most frequently found in hereditary diffuse gastric cancer, lobular breast carcinomas, etc. They are also mutated in a number of sporadic cancers of ovary, endometrium, thyroid, etc.


  Discussion Top


Cell division occurs in the multicellular organisms throughout their life. It is either to grow or to repair the lost cells. Protooncogenes regulate and produce proteins that regulate normal cell growth and development. Mutation that alters protooncogene may convert them from regulatory gene to cancer producing gene. [5] Various mechanisms play role in carcinogenesis.

Cancer cells develop self-sufficiency in growth signals, by various mutations. They may start producing growth factor themselves and respond by proliferation (autocratic action). The example is glioblastoma, where it secretes PDGF and expresses PDGF receptors. [3] On the other hand, mutated gene may deliver continuous mutagenic and proliferative signals to cells and they go on proliferating even in absence of relevant growth factor. [12]

The example is amplification of HER-2/neu receptors in carcinoma breast and over expression of EGF receptors in carcinoma lung. Mutated gene can also cause cell to achieve growth autonomy by encoding various components of signaling pathways of growth factor receptors. RAS and ABC oncogene are examples of such phenomena.

The tumor suppressor gene functions, in a unique way, in cell division cycle. p53 and RB gene is most studied gene. In mutated p53 and RB gene, they are rendered nonfunctioning and cell division progresses to produce carcinogenic material. They can be corrupted by certain viruses like HPVs, HBV, and possibly EBV, etc. The growth factor pathway (TBG-β) may be impaired in cancer of colon and pancreatic cancers. They are also responsible for inheritance of certain cancers like  Li-Fraumeni syndrome More Details and adenopolyposis colon cancers.

Apoptosis is programmed cell death. By this the damaged cells are eliminated. In human cancers, aberrations in apoptotic programs occurs and the damaged cells do not undergo apoptosis as usual.

Cancer cells become immortal by unlimited replicative potential. The escape from cellular senescence and becoming immortal by activating telomerase, or an alternative mechanism to maintain telomere, constitutes an additional step in oncogenesis. Telomerase has been examined in hundreds of studies as a potentially sensitive biomarker for screening, early cancer detection, prognosis, or in monitoring as an indicator of residual disease. [11]

Like any other normal tissue, tumor cells also require rich supply of nutrients and oxygen for sustained growth and replication. It happens through angiogenesis. Lymphangiogenesis is also brought about by VEGF family. This knowledge is used to develop anticancer therapy by blocking angiogenesis. One such angiogenesis inhibitor monoclonal antibody, bevacizumab, is approved by USFDA for use in certain cases of glioblastoma and other cancers like colorectal cancer, non-small cell lung cancer, metastatic renal cell cancers, etc.

Metastasis or dissemination of cells to distant organs is a distinct feature of cancer cells. Development of metastatic potential involves several stages. They first become loose, local degradation of basement membrane occurs next. Then cells get attached to new ECM components to promote invasion and metastasis. Dissemination is final step of migration. This occurs by local spread or through blood stream and lymphatics. They invade new organs and tissues. There they may establish new vascular connection and thus the metastatic process goes on.

The genomic instability seems to be the basic cause of carcinogenesis. This genomic instability is due to defect in DNA repair. [9] During DNA replication the errors are corrected by several processes. [7] One of them is mismatch repair. The example of this is HNPCC, where germline mutations have been identified in several genes. [4]

Other mechanism is defective nucleotide excision repair system. In patients with xeroderma pigmentosa the damaged gene is prevented from being repaired due to defective system. Yet another way to bring about genomic instability is defective recombinant repair.

This process is predominant in hereditary breast cancer due to mutation in BRCA-1 and BRCA-2 genes.

Mutation in RB gene product causes defect in transcription during cell division. Deletion or mutation of PTEN tumor suppressor gene is found in a number of carcinoma of breast, prostate, and kidney; CD; multiple hamartomasyndromes; etc. Mutation of P16 gene is found in about 20% of melanoma prone families, cancer of pancreas, esophagus, stomach, breast, colon, etc. Mutation of E-cadherin is found in hereditary diffuse gastric cancer, lobular breast carcinoma, carcinoma ovary, thyroid, etc.

This is amply clear by the ongoing discussion that defect in gene and so in the gene product is in the heart of carcinogenesis. Studies of these mutations and defects may open new vistas to find out the cure for cancers besides surgery, radiotherapy, and chemotherapy.

 
  References Top

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Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 2011;17:347-62.  Back to cited text no. 10
    
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Li FP, Fraumani JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty four kindreds. Cancer Res 1998;48:5358-62.  Back to cited text no. 14
    
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