The Molecular Basis of Cancer

Introduction

Cancer refers to a group of diseases typified by unregulated growth of cell and the spread and invasion of cells from the primary site or site of origin to other parts of the body. Cancer development involves a multistep process which needs the multiple genetic mutations accumulation in a single cell which presents neoplastic cell typical features. Tumor cells are characteristically different from normal cell since they demonstrate uncontrolled growth.

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About 85% of cancers happen in epithelial cells and are grouped as carcinomas. However, cancer can occur in other cells including mesoderm cells, and glandular tissues. Cancers can be of distinct features and origin. In addition, the main factor which causes cancer in every target tissues varies extensively. Moreover, there are variations in the molecular mechanisms engaged in carcinogenesis in each type of cell and the cells spread pattern from the primary site. Hence different treatment may be needed for different cases. This paper focuses on summarizing the cancer biology.

Mutation

Cancer results from DNA sequence alterations. A large quantity of evidence demonstrates that the tumor cells DNA has a number of alterations ranging from large chromosomal aberrations that include chromosomal translocations and deletions to subtle point mutation. The cell mutations accumulation over time stands for a multi-step process which inspires carcinogenesis.

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The requirement for mutations accumulation over time explicates why there is increased cancer risk with age. About all tumor cells identified mutations are somatic mutations where in the somatic cell DNA has been damaged. The mutations however are not inherited by next generation of offspring, though after cell division, they are passed to daughter cells. Inheritable chromatin and genome structure modifications also play a part in carcinogenesis. Therefore at cellular level, cancer is regarded to be a genome disease, and thus only egg or sperm cells DNA alterations will be inherited by offspring.

Loss of genes Functions

There are three essential processes which contribute to the general net number of cells in an individual. These processes include cell proliferation which involves division of cells to create two daughter cells. This is followed by cells elimination through programmed death of cell which also affects net number of cells. The finally, the inactive phase which cells enter during cells differentiation process which can as well impact the net number of cells. The DNA mutation which can change the normal function of genes involved in differentiation, apoptosis, or growth can affect the cell numbers balance in the body and result to unregulated growth (). Cancer originates from a cell which has obtained genetic mutations in main genes regulating DNA repair, cell death pathways, and cell cycle. Consequently, tumors will progress to have cytogenetically diverse clones due to genetic instability initiated by the first mutations. It has been demonstrated that instability of chromosomes is an essential feature of a various kinds of cancer. It has been clear in the recent past that double stranded break of DNA and abnormalities of enzyme repair can enhance carcinogenesis. Actually, there is evidence demonstrating that deregulation of enzymes liable for DNA breaks repair can introduce lesions that might result to extensive genomic instability, resulting to cancer. This might happen when breakage of DNA strand happens and repair is bypassed and not done, if the cycle of the cell progresses either because of P53 signaling pathway abnormalities. The yielding cell clones are destined to have inherited some kinds of genomic perturbations.  

Oncogenes

Most of solid and haematological tumors are initiated by specific gene which enhances carcinogenesis usually regarded as oncogenes. These oncogenes are liable for production of genes, transcription factors, receptors, and growth factors engaged in apoptosis regulatory and chromatin remodeling factors. It is usually accepted that oncogenes are the main genes causing cancer. A study involving single cultured cells mined from non-transgenic mammary gland of mice and that assessed the oncogenes role in carcinogenesis and suppression of cancer in primary cancer cells was conducted with intention of determining the role of oncogenes in cancer development. 

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The study established that cells of mammary gland from mice expressing doxycycline controlled oncogenes kras and myc, lost their acini divisions and had augmented rate of cell proliferation, filling up the glands lumen, proposing cell cycle control loss and augmented cell proliferation. Moreover, when oncogenes are eliminated, the cells demonstrated a substantial decline in cell proliferation and the cells which filled up the lumen earlier went through programmed death of cell, with exception of cells located at the edge of the tumor. The study evidently illustrated that oncogenes play a great role in tumor regression and carcinogenesis. The study in addition demonstrates that cells at the tumor edge might survive the oncogene withdrawal effects by remaining in dormancy state till further events have taken place before another growth episode can happen. This mostly contributes in relapse of the tumor.

Tumor Suppressor

Tumor suppressor refers to molecules that are normally engaged in blocking tumor triggering signals. Various tumor suppressor genes have been evaluated for an obligation in cancer etiology for instance loss of mutation function in gene NF1 tumor suppressor that encodes neurofibromin has been said to initiate inherited cancer regarded as neurofibromatosis type 1. NF1 is also related to glioma development3. NFI has also been demonstrated to be created during progression cell cycle and degraded by Ras prompted during protein Kinase C (PKC) activation and hence PKC inhibition result to stabilization and accumulation of NF1 in various glioblatoma human cells in vitro.

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Tumor suppressor genes that are thought to be engaged in normal cellular proliferation suppression and employ a negative cell cycle regulation are usually inactivated in tumors. This function loss is either as a result of mutations, epigenetic changes or/and deletions. Mutations of tumor suppressor gene are recessive to usual allele therefore, imposing the second eilde-type allele inactivation for tumor formation. The determinants of germline of about all familial cancers are established to be mutant tumor suppressor genes alleles. Since there are safeguards created into the system, two or more mutations have to take place before formation of cancer.  

Apoptosis

The molecular basis of cancer also involves understanding apoptosis. Apoptosis refers to a programed death of cell that is usually involved in the maintenance and development of an organism. Apoptosis might be induced after a cell turns to be abnormal particularly during tumor and maybe during malignancy thus causing the death of abnormal cell. Nevertheless, the abnormal cell may fail to as a result of mutation which results to either malfunction of this kind of tumor gene suppressor as p53 gene, which is a gene which initiates apoptosis or excessive expression of this kind of proto-oncogene such as bcl-2 that generate large volumes of bcl-2 protein that deactivate apoptotic program. Lymphomas malignant originating from changed b-lymphocyte is initiated by bcl-2 gene mutation. 

Telomerase Activities

Molecular basis of cancer can also be explained in telomerase activities. Telomerase refers to RNA-related enzyme which synthesis telomeres, specific DNA sequences found at the chromosome tip that prevent the continuous DNA loss during the cell replication process. A norm cell contains replication period, and only stop diving when it ages. Tolemeres partially regulate the cell dying and aging process as they shorten each time cell divides and chromosomes replicate6. Once telomeres are shortened to a specific size, the cell attains a crisis point where it is prohibited from dividing anymore and hence it dies, thus working as tumor suppressor by initiating cell death. Equally, the telomeres shorting in a cell going through replication can be prohibited either through expression of oncogenic or tumor suppression activity inactivation. Telomeres in the transformed cell do shorten, though as the crisis point becomes closer, a telomerase enzyme which was previously inactive is activated and therefore stopping telomeres from further shortening thus prolonging the cell life. Actually activity of telomerase has been identified in over 90% of human cancer tumors that include ovarian, breast, prostrate, and colon cancers. Telomerase might in addition act to enhance tumor genesis through mechanisms which do not rely on telomere length. Therefore, tolemere length maintenance and telomerase activity are important replicative ability maintenance in cancer cells.  Once the telomeres are reduced past a specific point in normal cells, the telomere function loss results to activation of cell-cycle checkpoints which are dependent on p53, resulting to apoptosis or proliferative arrest. Transformed cells might however contain defects in checkpoints of cell-cycle, permitting critical shortening of telomere in dividing cells. These cells might survive with defects of chromosome that result to instability of genomic or die through apoptosis. Telomerase reactivation in cells containing abnormal genomes deliberates unlimited proliferative cells capacity which contains tumouri-genic ability. 

Epigenetic Perturbation

Epigenetic perturbation is another molecular basis process of cancer where expression of gene can be changed without altering the DNA sequence. It has more recently become clear that changes of epigenetic in the CpG islands close to the tumor suppressor genes promoter areas might as well add to genetic instability. Most of the researches have demonstrated that loci epigenetic changes that control various unique factors of transcription might yield to miss-interpretation of various histone codes and generate aspects that can dysregulate control machinery of cell cycle resulting to cancer. The research on the subject demonstrated that instability of chromosomes as a result of translocations might result to factors promotion which can disrupt methylation-readout or methylation status of some essential loci in the DNA resulting to cancer. Therefore, epigenetic perturbation might contain some significant implications in initiation of cancer.

Agiogenesis

Agiogenesis is another aspect involved in molecular basis of cancer. Based on research the survival and function of cell depend on nutrients and oxygen offered by the surrounding vasculature. This is factual not just for normal cells but their malignant counterparts too. Agiogenesis is said to play a vital role for tumor explants explosive growth. In addition, the research has also demonstrated that anti-VEGF antibody do impair neovascularization and growth of mice subcutaneous tumors. The angiogenic-switch, which refers to aptitude to sustain and induce angiogenesis appear to be a discrete step in development of tumor, resulting to an alteration in the inducers balance and angiogenesis inhibitor.

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Most tumors have been demonstrated to have an increased FGF or/and VEGF expression, which are both strong angiogenesis stimulators, comparative to their non-malignant equivalents, while others show a decreased angiogenesis inhibits expressions that include interferon β2 and thrombospondin- 1. The mechanisms fundamental to these shifts in expression of gene are not effectively understood. However, since tumor angiogenesis might play part in majority of solid tumors, it provides an attractive therapeutic objective and the anti-angiogenic strategies research has already resulted to multiple clinical trials.

Metastasis and Invasion

Metastatic disease represents 90% of adults’ cancer deaths. Although this might not be the case with children who the main malignancies are brain tumors and leukemia, it still shows the situation among children established to have solid tumors. To fruitfully produce a metastatic tumor, beyond the already discussed characteristic of cancerous tumor, the malignant cell requires the aptitude to leave the basic tumor, drift into blood circulation, live there, exit the blood circulation system and proliferate and settle in a new microenvironment. Although the extra cellular integrins, cadherins, and pro-invasion is being invested intensively, the molecular mechanism and regulatory circuits controlling this process persist to be elusive. 

Targeted Molecular Therapy

Agents utilized in targeted cancer therapy inhibit specific signaling pathways and receptors which enhance growth of tumor cells. These agents comprise of tyrosine kinase inhibitors (TKIs) small molecule and monoclonal antibodies. The tyrosine kinase family receptor includes families of platelet-derived growth factor receptor (PDGFR), epidermal growth factor (EGF), vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). These therapeutic agents obstruct signaling of receptor tyrosine kinase by binding to the growth receptors extracellular component. The agents can bind the ligand which initiates the bind or receptor intracellular sites which interfere with downstream events of signaling. The targeted agents’ toxicity profiles differ considerably from those of standard chemotherapy since they do not obstruct DNA replication.

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