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Molecular Carcinogenesis - A Detailed Review

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Cancer is the uncontrolled growth and proliferation of cells. Read the article below to find the molecular basis of cancer formation.

Medically reviewed by

Dr. Rajesh Gulati

Published At November 24, 2023
Reviewed AtNovember 24, 2023

Introduction

Cancer is uncontrolled cell division. The cancer cells have the ability to have uncontrolled division. Carcinogenesis is a multiple-step phenomenon. Cancer formation involves the accumulation of various genetic modifications. These genetic changes include activating proto-oncogenes to oncogenes, deregulating tumor suppressor genes, and DNA repair genes.

What Is Cell Cycle and Apoptosis?

In normal cells, proliferation and progression are controlled by groups of proteins. Proteins interact in a particular sequence of events. Cyclin-dependent kinases (CDKs) are 'master protein kinases' that help progress through the cell cycle's different phases by phosphorylating and activating other kinases. CDK activity is based on activating units. These activation units are called cyclins, synthesized and degraded in a cell cycle. CDK inhibitors regulate cyclin-CDK complexes. The repeated entry of cells into the cell cycle is caused by extracellular mitogenic signals transmitted through the signaling pathways to regulatory proteins, like transcription factors in the nucleus. These regulatory proteins activate the S-phase CDKs, which start the synthesis of DNA.

In normal cells, activation of the transcription factor, p53, is termed the ‘guardian of the genome.’ This factor can cause cell cycle arrest and induce apoptosis by induction of the expression of cell cycle inhibitors, which prevents the proliferation of a cell - initiation of apoptosis in too much damage and beyond repair situations. Inactivation of the p53 protein disrupts the apoptosis signal and increases the survival of cancer cells.

What Is Cell Immortalisation and Tumorigenesis?

Immortalization is the gain of an infinite lifespan. Normal mammalian cells proliferate a limited number of times before aging. Immortalization depends on telomerase, the enzyme that maintains telomeres at the ends of chromosomes. Normal cells lack detectable levels of telomerase activity; a higher number of tumors consist of active telomerase enzymes.

How Does Cell Signaling Occur in Carcinogenesis?

Growth factors play an important role in the normal growth control process by maintaining tissue homeostasis. They transmit growth signals. Specific growth factor receptors (GFRs) receive these signals on the cell surface. GFRs transfer the growth signal through the signaling pathways and activate target molecules to start proliferation.

Cancer cells can induce their own growth stimulation signals. When EGFR gene mutation occurs, activation in the absence of GFs or overproduction of GFs leads to an autocrine signaling loop. Cancer cells can become GF-independent by involving the activation of internal signaling components.

Which Genes Are Frequently Mutated in Cancer?

The genes that are involved in carcinogenesis are divided as follows:

  • Oncogenes act as cell accelerators.

  • Tumor suppressor genes act as cell brakes along with DNA repair genes.

Genes that promote cell growth in cancer cells are called oncogenes, and their regular counterparts are proto-oncogenes. Proto-oncogenes are regulators of cell proliferation and differentiation. Oncogenes can encourage cell growth even in the absence of growth signals. Proto-oncogenes can be converted to oncogenes through point mutation and gene amplification. This can lead to the overproduction of growth factors, increased replication signals, and uncontrolled stimulation in the existing pathways. The Rat Sarcoma Virus - RAS oncogene is the most frequently mutated oncogene. Ras functions as an on-off 'switch' for critical signaling pathways and controls cellular proliferation. Usually, Ras is activated occasionally to activate the MAP-kinase pathway, which transmits growth-promoting signals to the nucleus. When the mutant Ras protein is permanently activated, it causes continuous stimulation of cells. The normal cell transforms into a cancer cell with the loss of function of tumor suppressor genes and defective gene copies, which promote tumor development.

What Are the Causes of Cancer?

Mutations: Cancer development involves continuous mutations over time. The basal mutation rate is lower in humans but can increase due to chemical mutagens, radiation, and tumor viruses.

  1. Chemical mutagens modify DNA. These changes are brought about by the alkylation or deamination of DNA bases or by intercalation between base pairs and the formation of DNA adducts.

  2. X-rays and radioactive radiation induce DNA double-strand breaks. UV radiation forms pyrimidine dimers.

  3. Certain viruses induce cancer development. Tumor viruses cause persistent infections in humans. Viruses are not complete carcinogens; they require additional factors to cause carcinogenesis.

What Is Multistep Carcinogenesis?

Carcinogenesis is a complex micro-evolutionary process. It needs the accumulation of genetic mutations. The mutated cells acquire new characteristics, advantages in growth, enhanced survival, and invasiveness. Three stages of carcinogenesis include malignant transformation, invasion of neighboring tissues, and metastasis:

  • Invasion and Metastasis: The cancer cells can spread to distant parts of the body through blood or lymph. This spread is called metastasis. Metastatic cells have lesser adhesion than normal cells and can degrade and penetrate tissue barriers like extracellular matrix (ECM) and the basement membrane of blood vessels.

  • Acquisition of Local Invasiveness: Invasion of the cell into blood or lymph vessels. They are transported through the blood or lymph vessels to distant tissue sites where they can escape the cancer cells from circulation. Cell invasiveness increases due to the overexpression of matrix metalloproteinases (MMPs) that degrade components of the ECM.

  • Angiogenesis: Angiogenesis is the growth of new blood vessels. Tumors release different proteins and many small molecules as signals for angiogenesis. These proteins include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).

  • Stromal Microenvironment and Carcinogenesis: Stromal cells in the extracellular matrix and tumor cells are also crucial for carcinogenesis. Matrix components break down to release angiogenic factors called vascular endothelial growth factors. VEGF induces vessel growth, and proteolytic factors help in cancer cell motility. The extracellular matrix stores growth factors. These growth factors are in inactive forms. Active matrix proteases release growth factors and stimulate tumor cell growth. Stromal cells present in the extracellular matrix transmit oncogenic signals to tumor cells.

  • Genetic Instability of Tumor Cells: Genetic analysis shows genetic abnormalities, like aneuploidy and chromosome translocations. This is due to the lack of active p53 protein and apoptosis-resistant cancer cells. Three different altered genetic mechanisms are explained below:

  • Loss of Heterozygosity (LOH): The human karyotype is diploid, and mutation of one allele of a tumor suppressor gene cannot cause cancer. In heterozygous individuals, the wild-type allele provides for a functional phenotype. However, through the missegregation of chromosomes, this cell loses its 'heterozygosity' and causes a cancerous phenotype.

  • Microsatellite Instability (MIN): This is seen in colorectal cancer cells with defective DNA mismatch repair systems.

  • DNA Hyper or Hypomethylation: DNA methylation of gene promoter regions cytosine-phosphate-guanine sequences is a control mechanism to stop specific genes.

  • Inherited Predisposition to Cancer: A wide range of rare familial syndromes affects family members' cancer. A far more significant number of familial cancer syndromes is based on mutations of tumor suppressor genes. They arise during gametogenesis, but the mutant alleles are typically dominant at the cellular level, which results in the disturbance of normal embryonic development and decreased viability of these embryos.

Conclusion:

Tumor markers cannot be the primary basis of a cancer diagnosis. The p53 gene - the molecular mass of protein products is the most important in human cancer. This tumor suppressor gene is mutated in half of cancer cases. The molecular basis of cancer gives us insight into the prevention of cancer. With an understanding of the molecular basis, we can determine if specific molecular changes in premalignant and malignant cancers can guide the treatment plan.

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Dr. Rajesh Gulati
Dr. Rajesh Gulati

Family Physician

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carcinogenesis
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