Tumor Dormancy, Metastasis, and Cancer Stem Cells - Research Paper Example

?“Cancer” Introduction Cancers initially progress from the normal cells and gradually gain the potential to multiply unusually and ultimately become malignant. These malignant cells proliferate clonally and form tumors which in due course impend to turn metastatic. Cancer, also known as malignant neoplasm, the hallmark characteristic involves uncontrolled proliferation of cells. Under normal conditions cell grow, divide and die, but in cancer cells the defect takes place at the gene level leading to the formation of an abnormal DNA. As genes are the basic control machine of the cell, alteration of any kind may bring devastating consequences, or malignancy. Moreover, in normal cells damage of any kind is taken care by the repair system but in cancer cells the repair function is also altered, thereby no repair of the damaged DNA occurs, cells divide continuously without displaying senescence hence, generating series of abnormal cells. (Normal cell cycle) (Genetic mutation- causes alteration in genes) (Alberts, 2007) "Cancer" the terminology has wide spectrum as it encompass a large group of cells, varied tissues and organs. Cancer is a genetic phenomenon that onsets as a result of trigger in the signal transduction of normal cell cycle, causing alteration in the cellular pathways for uncontrolled proliferation figuring malignant tumors. Cancer cells are not confined to one location and they turn invasive, spread to the nearby tissues initially and gradually their seedlings are carried to different parts/ organs of the body via lymph or blood causing invasion of the cancer to other tissues and organs. This stage is called metastasis. On the contrary, in some cases cancer cells do not display uncontrolled growth, they are non-invasive and do not spread, such stage of cancer only forms benign tumors. Classification of cancer According to National Cancer Institute, cancer encompasses as many as 100 different kinds. They are named on the basis of organ they are associated with or the origin of the cell, e.g. cancer that is initiated in colon is known as colon cancer while basal cell carcinoma is the name given to the cancer that is initiated in the basal cells of the skin. Classification of cancer includes numerous categories- Carcinoma- Cancer that is initiated in the skin or the lining of the internal organs. Sarcoma- Cancer that is initiated in mesodermal tissues encompassing bone, cartilage, muscles, blood vessels or any connective tissue. Leukemia- includes cancers that onsets its proliferation in blood- forming tissues, bone marrow leading to the formation of abnormal blood cells. Lymphoma and myeloma- Involves cancer that onsets in the immune system cells. Central nervous system cancers- involves the uncontrolled proliferation that occurs in the tissues of nervous system, brain and spinal cord. Germ cell tumor encompassing pluripotent cells present in germ line. Blastoma- involves cancer of embryonic tissues (National Cancer Institute). Factors influencing the cancer formation 1. Environmental factors- tobacco and alcohol consumption may trigger the proliferation of cancer cells. 2. Obesity- sedentary life style and higher intake of calorific fast food may lead to the trigger of cancer genes (Bassen- Engguist, 2011). 3. Alteration in the environment, due to pollution of the atmosphere, release of obnoxious agents with carbon particles including polycyclic aromatic hydrocarbons from the industries, release of household as well as industrial waste into the rivers making the water unfit for consumption, may harbour various chemical agents may act as carcinogens, causing cancer. 4. Genetic factors especially genetic susceptibility for cancer due to genetic polymorphism leading to the interaction of genes with the environmental agents. 5. Radiation hazards encompassing UV, radioactive radiations, xenochemicals etc may act as carcinogenic agents. 6. Various microbes, viruses like hepatitis B and hepatitis C virus are known to be associated with hepatocellular cancer, HIV is associated with Hodgkin's and non Hodgkin's lymphomas, human papillomavirus is associated cervical cancer, Ebstein-Barr virus is associated with nasopharyngeal cancer. Virus induced neoplasia is directly influenced by host and environmental factors that are capable of modulating the process of cellular transformation (Katzang, 2009). 7. Food items especially preserved food or food additives, pesticides, dioxins, organochloro, Organophosphorous compounds may act as carcinogenic agents. 8. Cosmetic agents- especially hair dyes may act as carcinogenic agents (Irigaray, 2007). Cancer Proliferation Cancer is initiated in the cell, the basic unit of any living entity. Under normal conditions the cell follow the regular cell cycle but any chemical, physical or biological agent may trigger the conversion of proto-oncogene to oncogene, the active form of cancer causing gene which is responsible for the altered metabolism of the cell. The genetic basis of cancer has been revealed through numerous animal models. The human Genome Project paved the way for an understanding towards information of the molecular basis essential to induce cancer. This aids in improving preclusion, analysis and management of cancer with better efficacy (Luo, 2008). The Cancer Genome Atlas aims at methodically differentiating the configurational source of cancer, through recognition of the genomic mutations linked with every cancer form. A corresponding progress and description forms the basis of understanding, growth and external appearance of the cancer or tumor called the phenotype of the cancer is essential for designing drugs that can potentially target the cancer cells (Luo, 2008). Luo et al (2008) have identified essential genes in 12 cancer cell lines, they were exploited to find the presumed and established oncogenes such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are vital for cancer cell proliferation and are found to be altered in the human cancers. Their findings postulate that tumoricidal agents trigger the expression of four genes PTPN1, NF1, SMARCB1, and SMARCE1. Moreover, five regulators are also activated in response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. The information is beneficial for pursuing future cancer studies as well as for therapeutics. Numerous evidence are available to establish the role of cancer stem cells in generating tumors and therefore understanding molecular machinery of the cancer stem cells is becoming an issue of paramount significance. It is instituted that genes are involved in eliciting signal transduction to alter the cellular pathways resulting in oncogenesis. A comparative study between normal stem cells and cancer stem cells states that signal transduction namely Bmi1 and Wnt are shared by the normal as well as cancer stem cells for cellular proliferation. Perception and thorough understanding for cancer stem cells will certainly aid in recognition of the drug targets and cancer therapeutics (Lobo, 2007). Basis of cancer- Normal stem cells characteristically slow in performing cellular cycling course for generating clone cells and follow normal mitotic cell division cycle, moreover the daughter cells produced are similar to the parent cells. Any mutation may result in abnormal proliferation and anomalous mitosis. Although mutations are generally insignificant and mutant cells are eradicated but accretion of mutation may occur in dividing cells resulting in cancer. Cancer causing mutation directly influence the cellular machinery including the genetic damage as well as signalling pathways and hence the entire cell division process is affected. As stem cells are pluripotent, long-lived as compared to their short lived descendant cells, they are vulnerable to the genotoxic elements causing oncogenic mutations (Pardal et al, 2003). Observations reveals that cancer tends to relapse after treatment. The genetic basis that has been postulated encompass the involvement of cancer stem cells. Research disclose that cancer stem cells play a pivotal role in cancer relapse as stem cells are not targeted by the conventional drugs and as these cancer stem cells are pluripotent they have potential to divide generating tumor again. Much understanding of the cancer could be procured with the help of cancer stem cells. As now research is directed utilizing cancer stem cells (CSCs), it becomes essential to understand the genetic basis of the cancer stem cells. (http://www.nature.com/bjc/journal/v103/n4/fig_tab/6605821f1.html#figure-title) According to CSCs theory, tumors possess cellular pecking order a misrepresentation of the normal cells, they display the ability of being pluripotent. The chief surveillances guiding to formulate the proposition that CSCs play vital role in proliferation as well as sustaining tumors encompass- Tumor heterogeneity stating that cells within the tumor are not alike. Only a few cells are cancerous while others are sensitive normal cells promoting the proliferation of the cancer cells. As mutation alters the characteristics of one cell, different cellular phenotypes could be observed in the tumor cells which may/may not show similarity with the cells from which it originated. Cellular heterogeneity prevalent in tumors is accredited to genomic unsteadiness directly influencing the tumor micro-milieu (Heng, 2006), and the major responsibility is shared by the cancer stem cells. Suggesting the self-regenerative ability of the cancer cells is due to its immense potential to rejuvenate and replicate. With the advent of technological tools and advances in stem cell research, the concept of stem cell prominence in tumorigenesis gained prevalence using distinctive stem cell markers namely, CD44, CD133 and aldehyde dehydrogenase. Recognition and isolation of cancer stem cells could be achieved for diverse tumors including blood, breast, brain, neck, colon, lung, pancreas, prostrate, head etc. Signalling pathways Further, elucidation of the pathways responsible for self-generation and cell destination in stem cells especially Wnt, Notch and Hedgehog, tumor suppressor gene PTEN (phosphatase and tensin homolog on chromosome 10) as well as TP53 (tumor protein p53) marks the similarity of the cancer-stem cell and normal stem cell, although in cancer stem cells, these pathways are deregulated promoting uncontrolled cell proliferation, displaying resistance for conventional therapeutic measures (Korkaya, 2007). While initial reports manifest the role of cancer stem cells in haematological malignancies, gradually it is now established that cancer stem cells are prevalent in solid tumors of breast, brain, colon and pancreas. Cancer stem cells are formed due to the alteration of stem cells, their characteristics define their self-renewal ability, their features like proliferation, the nature of their spread, rejoinder towards radio- and chemo-therapy. Resistance to induced apoptosis, radiations as well as cytotoxic agents is also displayed by stem cells but augmented resistance is shown by cancer stem cells and tumors. These actions of cancer stem cells are attributed to the re-commencement of varied growth promoting signalling cascades encompassing- epidermal growth factor (EGF) or EGFR; stem cell factor (SCF) or KIT, sonic hedgehog, Notch, cancer stem cells (CSCs) may or may not involve Wnt/beta-catenin. Resistance to therapeutic agents displayed by the cancer cells may also be attributed to augmented DNA repair and ABC carrier arbitrated drug efflux. Any alteration in the microenvironment of CSCs could also be one of the characteristic feature to manipulate the behaviour of cancer stem cells. Essentially, the current cancer therapeutic drugs are desired to progress in the direction to enhance the molecular targeting of tumor cells so as to sensitize them for the actions of conventional therapeutics leading to abrogation of tumors (Ischenko, 2008). Role of p53 The p53 is the most widely studied protein in relation to tumor proliferation. p53 tumor suppressor potentially restrict the progression of immature as well as mature neurons when the condition of cellular stress is sensed by the protein molecule. Any ambiguity related with the production of p53 or its inactivity, it culminates into CNS pathogenesis and formation of tumor. On the other hand, excessive production of p53 may lead to defect of neural tube, embryonic lethality, or degeneration of neurons. p53 is therefore the most imperative molecule that promotes as well as check the cellular proliferation, apoptosis, cessation of cell cycle and ultimately cell death, besides the most studied molecule, still a lot is required to be dwelled (Mendrysa, 2011). The level of p53 is therefore responsible for the survival and demise of the cell. p52 reactivation in brain tumor stem cell could be the possible therapeutic measure in future (Hede, 2011). Therapeutics Present cancer therapeutics encompasses tumor regression, these therapeutic measures may aim to eliminate distinguished tumor cells but are ineffective to eradicate cancer stem cells, unless CSCs are eliminated cancer proliferation and incidence of cancer relapse could not be controlled. This concept has brought a new paradigm in the cancer therapy and has created a research awareness to investigate further understanding of signalling pathways responsible for regenerative feature of cancer cells (Korkaya, 2007). Numerous therapies found to be targeting cancer stem cells encompasses- monoclonal antibodies (Okamoto, 2008), vaccines (El-Shami, 2008), apoptosis initiation by way of oxidative stress, NF-?B inhibition, as well as commencement of p53 (Guzman, 2007), drugs that aim Notch (Shih, 2007) and hedgehog (Zhao, 2009) signalling pathways play vital role in cancer therapy. Current remedial approach involves targeting directly the cancer stem cell (CSCs) as well as its micro-environmental position. A novel therapeutic strategy for targeting the cancer cells was suggested by Tang, et al, (2007) regarding consideration of the status of reactive oxygen species in the cancer stem cells and its potential role in eliminating cancer. An amalgamation with conservative therapeutics cancer stem cell targeting, absolute abrogation of cancer could be attained. In the present scenario, identification and characterization of CSCs, accountable for the formation of tumor in varied tissues, is of paramount significance. Evidence supporting the presence of cancer stem cells and their association in tumor proliferation are well documented. Prevalence of CSCs is reported for human leukemias, breast cancer and brain tumors (Passegue, 2005). After the primary treatment of tumor and its successful elimination, metastatic cancer cells can reappear after their dormant phase. This dormancy could vary from a few months to years. This happens due to the failure of the primary treatment procedure in eliminating the dormant micrometastases as well as solitary metastatic cells, highlighting the significance of metastatic dormancy. An understanding for CSCs and their roles in solid tumor could be beneficial in understanding the metastatic dormancy, which could have therapeutic implication in treating metastatic condition or tumor dormancy (Croker, 2009). Evolution of metastatic cancer stem cells could be genetic or epigenetic and vary due to the difference in cell surface markers. (Visvader, 2008). The primary therapeutics encompasses conventional therapies for cancer; focused on targeting the cluster of cells prevailing in cancer, these therapeutic measures gained prominence in regressing the cancer proliferation, even though complete eradication could not be accomplished since the conventional measures could not eliminate the extraordinary cancer stem cells, serving as the chief cause of cancer relapse. This resistance displayed by the cancer stem cells towards the conventional therapeutic methods is responsible for metastasis. 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