Molecular Targets and Cancer Therapeutics (Part 1) E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2009
Today, treatment options for cancer patients typically include surgery, radiation therapy, immunotherapy, and chemotherapy. While these therapies have saved lives and reduced pain and suffering, cancer still takes millions of lives every year around the world. Researchers are now developing advanced therapeutic strategies such as immunotherapy, targeted therapy, and combination nanotechnology for drug delivery. In addition, the identification of new biomarkers will potentiate early-stage diagnosis.
Molecular Targets and Cancer presents information about cancer diagnosis and therapy in a simple way. It covers several aspects of the topic with updated information on par with medical board levels. The book features contributions from experts and includes an overview of cancer from basic biology and pathology, classifications, surveillance, prevention, diagnosis, types of cancer, treatment and prognosis.
The first part of this book introduces the reader to cancer epidemiology, genetic alterations in cancer, exogenous and endogenous factors in carcinogenesis, roles for growth factors in cancer progression, cell signaling in cancer, transcription factors in cancer, and cancer genetics and epigenetics.
This comprehensive guide is a valuable resource for oncologists, researchers, and all medical professionals who work in cancer care and research.
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PREFACE
Oncology is a fast-evolving field. The last decade had witnessed enormous, complex discoveries in cancer biology, genetics, mutations, diagnostics and new targeted biological therapies. The team of expert contributors to this book tried to present these major aspects including, cancer traits, exogenous factors of cancer, the biology of cancer, growth factors of cancer, signaling pathways of cancer and epigenetic factors of cancer, in a simple but, at the same time, using up to date information. The book will be a great resource for medical students, scientists, physicians and other healthcare professionals involved in cancer care and cancer research.
Faris Q.B. Alenzi Professor of Immunology College of Applied Medical Sciences Prince Sattam Bin Abdulaziz University Saudi ArabiaDEDICATION
I dedicate this book to those who lost their lives because of this disease. May Allah bless them all!
To,
Fatema S. Albady Alanazi
Talal H. Almosaieed Alanazi
Saeed A. Baqader
Abdulla S. Alsiary
Moqaeem A. Alanazi
Nadda F. Alhassainan
Shaikha A. Alhabrdi
Hawazn W. Alnaam
Halah F. Alnaam
Hanan G. Alanazi
Eida S. Alhussani
Fryah A.M. Alshammari
Abdulrahman Zekri
Ghaytha Alshammari
List of Contributors
Introduction
Abdulaziz Bin Saeedan1,*,Mohd. Nazam Ansari1,Amal Almohisen2Abstract
Cancer is a complex family of diseases that usually begins with carcinogenesis, in which abnormal cells divide or develop wildly by not following the regular path of cell division and likewise can invade nearby tissues. Cancer cells demonstrate transformations in metabolism, which is frequently more anaerobic than normal and probably can tolerate hypoxic surroundings. The remarkable variability of the disease, at all levels, is the major challenge for cancer medicine. Six biological abilities gained during the multi-stage advances of human tumors are the maintenance of proliferative signaling, the prevention of growth suppressors, cell death resistance, replicative immortality allowance, angiogenesis induction, invasion, and metastasis activation. In this chapter, we discuss the features of cancer cells and the epidemiology of cancer for better understanding.
INTRODUCTION
The biological revolution of the 20th century completely redesigned all fields of biomedical knowledge, including cancer research. The revolution partially produced by Watson and Crick’s finding of the DNA double helix, which began in the mid-century, and continues to this day [1]. Furthermore, understanding its true significance and its long-standing ramifications is still in process. The stream of molecular biology, derived from this finding, provided answers to the most insightful problem of 20th-century biology and described how the genetic structure of a cell or organism determines its outlook and function [2].
Like many other biological disciplines, modern cancer research would have remained a theoretical science if this molecular foundation did not exist. By exploiting the evolution in the sciences of molecular biology and genetics, many
diverse biological phenomena, including cancer, currently have been partially explained. Surprisingly, it is also seen that most of the perceptions of the origins of malignant disease are out of the laboratory benches of cancer researchers. As a substitute, significant knowledge that drives the need to achieve rapid development in cancer research is delivered from the study of diverse organisms, ranging from yeast to worms to flies [3].
Definition
Cancer is a disease in which an assembly of abnormal cells divides or develops wildly by not following the regular path of cell division and likewise can invade nearby tissues. Persistent subjection of the normal cells to signals that control whether the cell should rest, divide into another cell or die. A degree of autonomy from these signals could result in uncontrolled growth and proliferation develops cancer cells. This could become lethal if this development continues and expands, leading to a major cause of cancer-related deaths owing to the spreading of tumors, and a procedure termed metastasis [4].
The concepts of modern cancer biology are based upon unpretentious principles. Fundamentally, all mammalian cells share analogous molecular networks that control cell proliferation, differentiation, and cell death. Ordinary cells are malformed into cancers as an effect of alterations in these networks at several levels, including the molecular, biochemical, and cellular ones. Such mechanisms for these changes are limited and can be determined.
In the past decade, phenomenal research developments in cancer have given us a perception of how cancer cells progress this autonomy. The present definition of cancer is that it is a disease that involves alterations or mutations in the cell genome. These alterations (DNA mutations) yield proteins that spoil the delicate cellular stability between cell division and quiescence, causing cells that keep multiplying to form cancers [5].
Characteristics of Cancer
Cancer is a complex family of diseases that usually begins with a process called carcinogenesis. Such a complex process involves converting an ordinary cell into a cancer cell in the body. The cancer cells display cellular and nuclear pleomorphic, then lose normal arrangement of cells, therefore developing alterations in the cell membranes and organelles, and hence exhibit abnormal mitoses and chromosomal abnormalities [6].
Intervallic cellular adhesiveness (for the solid surface) and contact inhibition (amid cells) may be the consequences of alterations in the cell surface glycoproteins and the underdeveloped tight junctions and desmosomes in malignant cells. Fluctuations in motility, adhesiveness, and contact inhibition possibly will promote invasion and the consequent formation of secondary malignant development metastasis.
Compared to a normal cell, cancer cells demonstrate transformations in metabolism. This metabolism of malignant cells is frequently more anaerobic than compared to normal hastily separating cells and is immensely speeded. Malignant cells can probably tolerate hypoxic surroundings. Glucose and amino acid uptake might be greater than before. These cells have extraordinary levels of hexokinase accumulation in their glucose consumption. In this scenario, the cancer cells lose the ability to synthesize specialized proteins distinct from segregated cells. Tumor growth is based on enzymes and other proteins produced by cancer cells [6].
The Hallmarks of Cancer
The remarkable variability of the disease at all levels, is the major challenge for cancer medicine. In the fall of 1999, Robert A. Weinberg and Hanahan depicted there were no credible organizational rules for the biological characteristics of tumors. In January 2000, they published an article “The Hallmarks of Cancer” to summarize these rules. The hallmarks of cancer constitute a fundamental belief that may deliver a rational basis for refining this complexity to better understand the mechanisms of the disease in its various manifestations [7].
For rationalizing the dynamics of neoplastic disorder, the hallmarks represent an organizing concept. Six biological abilities gained during the multi-stage advances of human tumors are the hallmarks of cancer. They comprise the maintenance of proliferative signaling, the prevention of growth suppressors, cell death resistance, replicative immortality allowance, angiogenesis induction, invasion, and metastasis activation. Underlying these hallmarks is genome instability, which produces the genetic variation which fast-tracks their acquisition, and inflammation, which nurtures several hallmark roles. Former era, conceptual advancement has added two emerging hallmarks of future generality to this list: energy metabolism reprogramming and evading immune destruction [7]. Apart from cancer, cell tumors demonstrate another measurement of complexity: they include a repertoire of engaged, ostensibly normal cells that contribute to the acquisition of hallmark characteristics by creating the “tumor microenvironment”. Increasingly, awareness of the extensive application of these ideas will inspire the creation of innovative ways of treating human cancer.
The conceptualization includes eight acquired abilities-cancer hallmarks, and two generic neoplastic disease characteristics that promote their acquisition during the multi-stage neoplastic growth and malignant progression phase. Numerous cell types inhabiting the tumor microenvironment, including heterogeneous populations of cancer cells, especially cancer stem cells, and three prominent groups of stromal support cells, are part of integrating these hallmark competencies into the symptomatic disease. One assumption is that cancer hallmarks are a valuable heuristic method for determining the mechanistic basis and interrelationships between various types of human cancer with future cancer therapy applications [8].
Features of Cancer Cell
Cancers or Malignant neoplasms have numerous unique characteristics that facilitate the experimental cancer biologist or pathologist to distinguish them as not normal. Epithelium (The External or internal surfaces covering cells of the body) is the origin of the most common types of human neoplasms [9]. The sympathetic stroma of blood vessels and connective tissue are available in these cells. Malignant neoplasms may look similar to normal tissues in growth and development in the early stages. Neoplastic cells can grow in any body tissue that comprises cells with the capacity for cell division. Their cultivation rate is frequently based on the surrounding normal tissue and may cultivate fast or slowly. Though this is not a static feature, the degree of cell renewal in several normal tissues (such as hair follicles, bone marrow, and gastrointestinal tract epithelium) is as swift as that of a fast-developing tumor. Neoplasm means “novel growth”, and is frequently mentioned and renamed with the word “tumor” to indicate a cancerous growth, to be more specific. Tumors can be classified into basic categories of two types: benign and malignant. The capability of classifying benign and malignant tumors is essential for providing appropriate treatment and prognosis for the patient with a tumor. The characteristics which differentiate a malignant tumor from that a benign tumor are as follows [10-12]:
1. Malignant tumors have the capability to invade and destroy neighboring normal tissue, whereas benign tumors develop by spreading out, do not attack surrounding tissue and are usually encapsulated. Benign tumors could become highly dangerous in certain cases. One of which is if the benign tumors press on nearby nerves or important blood vessels (might push aside normal tissue), or amend normal homeostatic mechanisms by releasing different biologically active elements, such as hormones.
2. Malignant tumors spread to other sites in the body using blood circulation or the lymphatic system and metastasize whereas, benign tumors remain localized and do not spread to other sites in the body.
3. Malignant tumor cells are likely to be “anaplastic”, or scarcely distinguished from normal cells of the tissue in which they originate. Benign tumors typically look like normal tissue when compared to malignant tumors. A few malignant neoplastic cells resemble the normal tissue at first structurally and functionally in which they originate. As the malignant neoplasm evolves in the course of time, it enters neighboring tissues, and metastasizes, and the malignant cells could look different from the original cell. The growth of a least distinguished malignant cell in a population of differentiated normal cells in some cases is called dedifferentiation. This word is possibly inaccurate for the procedure, due to the implication that a differentiated cell goes backward in its evolving procedure after carcinogenic abuse. The anaplastic malignant cell type is more likely to emerge from the posterity of a “stem cell” tissue (the one that continues to show renewal potential and cannot be completely differentiated) that has been choked or redirected in its course to form a fully differentiated cell. Examples of neoplasms that retain a differentiation modicum include pancreatic islet cell tumors that still make insulin, gland-forming colonic adenocarcinoma cells, such as epithelial structures and secrete mucin, and breast carcinomas that make abortive attempts to shape structures that imitate ducts of the mammary gland.
Conversely, the response controls handling normal tissue development or negative physiologic response handling hormonal secretion do not respond to Hormone producing tumors. For instance, in the face of severe hypoglycemia, and lung carcinoma-producing ectopic adrenocorticotropic hormone (ACTH), an islet cell tumor may continue to secrete insulin and possibly will continue to harvest ACTH while circulating levels of adrenocortical steroids are adequate to induce Cushing's syndrome. Many malignant neoplasms, predominantly the aggressively developing and invasive ones, only imprecisely look like their regular counterpart tissue structurally and functionally. Hence are believed to be “undifferentiated” or “badly differentiated.”
4. Malignant tumors develop very quickly compared to benign tumors. Malignant tumors usually display signs of significant development with the association of neighboring tissue once they reach a clinically detectable stage, over weeks or months, while benign tumors have a slower rate of growth in years.
5. Normal cells need mitogenic growth signals before they can transit from a peaceful tranquil state to a dynamic proliferative state. Cancer cells encourage their own growth. Cancer cells may also change the integrins (extracellular matrix receptors) they express, favoring those that transmit pro-growth signals.
6. Cancer cells fight inhibitory signals that would otherwise halt their growth; however, anti-proliferative signals in normal tissues promote cell quiescence and tissue homeostasis. Cells could be forced out of the active proliferative cycle and into a peaceful (G0) state, from which they could reemerge when extracellular signals allow. If cancer cells are to thrive inside the body, they must be able to evade these anti-proliferative signals.
7. When a cell is activated by a variety of physiologic signals, apoptosis is triggered in a series of steps in which cell membranes are disrupted, the cytoplasmic and nuclear skeletons are broken down, the cytosol is removed, the chromosomes are debased, and the nucleus is fragmented, all within 30–120 minutes. Cancer cells can develop resistance to apoptosis through a variety of methods. Cancer cells that have lost proapoptotic segments are more likely to hold others that are identical.
8. To keep dividing indefinitely, cancer cells need a mechanism to maintain their telomeric DNA (immortalization). Telomeres, like the rest of a chromosome that contains its genes, are DNA sequences — chemical code chains. Cells can divide 50 to 70 times on average, with telomeres becoming shorter and shorter before the cells become senescent or die. Before a cell may differentiate, it duplicates its chromosomes so that the genetic material of both new cells is indistinguishable. A chromosome's two DNA strands must unwind and split in order to be repeated. Telomerase is a naturally occurring enzyme that promotes the repair of telomeres. It is active in stem cells, germ cells, hair follicles, and 90% of tumor cells, but its expression in somatic cells is poor or non-existent. Telomerase adds bases to the ends of telomeres to make them longer. Telomere maintenance is evident in a wide range of cancer cells.
9. Blood vessels provide oxygen and nutrients, which are critical for cell capacity and survival. Angiogenesis, or the development of blood vessels, may be aided or hindered by the balance of positive and negative signals.
10. Metastases are responsible for 90% of cancer deaths in humans. Cancer cells with the ability to invade and metastasize can escape the primary tumor mass and colonize new territories in the body, where nutrients and space are not restricted at first.
Cancer cells have been shown to exploit angiogenesis to improve blood supply to the tumors. This represents a key step in tumor expansion.
Epidemiology of Cancer
The epidemiology of cancer is defined as the study of cancer’s classification based on various aspects such as sex, age, economic status, etc., and these features determine its dominance. In the past decade, the mortality from cancer has altered from a trivial to a major. In addition, it could be clearly seen that it differs from country to country and changes the cancer risk; variants of disease among geographic landscape shift significantly [13]. Causes of cancer vary based on personal hygiene to life style, for example, cigarette smokers proclaim to have a higher risk of cancer than non-smokers. One of the basic characteristic necessities for effective epidemiology classification is population-based cancer archives which provide the required graphic information on the population [14].
Cancer is already a major problem in different geographic locations, and lifestyle changes fundamentally mark the increasing rates. The available data projections show a rise in aging together with accelerating growth of population; this forecasts that the problem will emerge bigger in the future [15].
Cancer Epidemiology in the World
Classical epidemiologic studies have enlightened with various facts that gave influential aids to classifying the etiology of commonly known cancers. These contributions show there has been a substantive impact on public health. The best-known associations are smoking and lung cancer, and this has motivated cancer prevention initiatives and policy changes widely and spread successfully. In northern parts of America and Western parts of Europe in the midst of the last century, various studies based on lung cancer were published, leading to the assumption that smoking was a significant reason for lung cancer in 1950. Similarly, the chemical industry based in Brittan studied the influence of chemical exposure at the start of the 1950s [8]. At the same time, Cornfield [16] and Mantel et al. [17] influenced the methodologic and investigative objectives of the case-control study design. Subsequently, Substantial data on the etiologic roles of explicit lifestyle, viral, work-related, and dietary risk influences in a range of cancers have been provided through many group and case-control studies. The International Agency for Research on Cancer (IARC) weighed the potential of 900 likely candidates for the cancer-causing and classified them into the following clusters (IARC- Report 9) [18]:
Cluster A: Carcinogenic to humansCluster B1: Possibly carcinogenic to humansCluster B2: Possibly a category of carcinogenic to humansCluster C: Cannot be classifiable as carcinogenicity in humansCluster D: Possibly not carcinogenic to humansEven though there are a lot of recognized developments in this field of study, we still have a long way to go, as we are on the verge of developing molecular tools to discover these relations. Furthermore, environmental challenges have a direct effect on the genes due to interactions and might modulate genetic properties. DNA damaging could be caused due to environmental exposures and in addition to may also modify gene expression through epigenetic reversible mechanisms is increasingly being recognized as a fact.
Cancer Epidemiology in the Kingdom of Saudi Arabia
Cancer is the 2nd largest cause of death worldwide and is accountable for more than 9.6 million deaths in about 185 countries [19]. Studies reported in the past 25 years on cancer incidence in Saudi Arabia were limited because of the small number of cases 1-12 available in most investigations [20, 21].
The first epidemiological study of cancer which includes over 11,000 consecutive cases seen in one institution in Saudi Arabia (Table 1.1). In 2018, there were 10,518 cancer-related deaths, and to add on, new cases found were 24,485 in Saudi Arabia amongst the whole population of 33,554,333 [22]. The commonly known cancers comprise breast cancer, colon-rectum (CRC), and prostate. The various cancers accounted for in the region of Saudi Arabia; some cancers magnitude epidemiology has risen drastically in recent years. This escalation might be endorsed to new policies and lifestyle adaptations in the Saudi population. Lack of knowledge and awareness of cancer, deficiency in screening & timely detection programs, and social barriers on the road to cancer investigations could be looked into with great importance. Apparently, risk factors for cancer in Saudi Arabia are due to obesity, iodine & Vit-D deficiency, genetics, use of tobacco, inactive lifestyle and viral infection [23, 24].
In recent years, Saudi Arabia has evolved tremendously due to rapid technological and economic development. The health resources have increased dramatically, and with enhancements in the national vaccination program and eventual control and reduction of communicable diseases, life expectancy is increasing and with it, the number of older people in the population. Hence, the incidence of chronic disease and cancer in Saudi Arabia will increase concurrently [25-27].
Cancer Registries
Cancer registries extract cancer-related clinical data from patient medical records. These registries provide data to state and national public health organizations in order to monitor cancer diagnosis and care patterns [28]. In the Kingdom of Saudi Arabia, Cancer Incidence Report is published annually by The Saudi Health Council (SHC), which is a collaborative effort by the team of the Saudi Cancer Registry (SCR). SCR is a population-based registry that seeks to identify cancer incidence, prevalence, and patterns in Saudi Arabia in order to aid clinical and epidemiological research and facilitate the assessment of appropriate national programs and activities such as cancer screening and early detection [29].
CONCLUSION
Cancer is a complex disease that usually involves alterations or mutations in the cell genome (carcinogenesis), leading eventually to uncontrolled growth, then invasion and metastasis. During recent decades, there has been a steep increase in cancer rates in most countries, making cancer one of the major health issues for health service providers. By exploiting the recent advances in cell and molecular biology technologies, many cancer development mechanisms can be revealed and understood, leading to the establishment of novel cancer therapeutic approaches.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
The authors are thankful to Syed Nasrullah for his valuable help in writing this chapter.
REFERENCES
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Cancer 1979; 44(4): 1543-8.[http://dx.doi.org/10.1002/1097-0142(197910)44:4<1543::AID-CNCR2820440456>3.0.CO;2-N] [PMID: 498028][25]Amer MH. Pattern of cancer in Saudi Arabia: a personal experience based on the management of 1,000 patients (part I). King Faisal Spec Hosp Med J 1982; 2(4): 203-15.[26]El-Akkad S. Cancer in Saudi Arabia: a comparative study. Saudi Med J 1983; 4(2): 156-64.[27]Amer MH. Epidemiologic aspects of esophageal cancer in Saudi Arabian patients. Ann Saudi Med 1985; 5(2): 69-77.[http://dx.doi.org/10.5144/0256-4947.1985.69][28]National Cancer Institute, “What is a Cancer Registry?” https://seer.cancer.gov/registries/cancer_registry/cancer_registry.html Last Viewed on May 10, 2021[29]Saudi Health Council - National Health Information Center: Saudi Cancer Registry Cancer Incidence Report, Saudi Arabia 2015. https://nhic.gov.sa/eServices/Documents/E%20SCR%20final %206%20NOV.pdfLast Viewed on May 10, 2021Cancer Traits; Present and Future
Khalid A. Asseri1,*,Afaf Ahmed Aldahish2Abstract
This chapter on “Cancer Traits; Present and Future” begins with a description of the process of carcinogenesis and, finally, the abnormal process leading to carcinogenesis.
Cancer is a multi-step mechanism in which cells undergo biochemical and behavioral changes, causing them to proliferate in an unnecessary and untimely manner. These changes occur from modifications in mechanisms that regulate cell proliferation and longevity, relationships with neighboring cells, and the ability to escape the immune system. Modifications that contribute to cancer require genetic modifications that alter the DNA sequence. Another way to alter the program of cells is to adjust the conformation of chromatin, the matrix that bundles up DNA and controls its access through DNA reading, copying and repair machinery. These modifications are called “epigenetic. The abnormal process that leads to carcinogenesis includes early mutational events in carcinogenesis, microRNAs in human cancer and cancer stem cell hypothesis, Contact inhibition of proliferation, autophagy, necroptosis, signaling pathways, telomere deregulation, microenvironment, growth suppressors evasion, resisting cell death and sustained cell survival, enabling replicative immortality through activation of telomeres, inducing angiogenesis, ability to oppose apoptosis, and activating invasion and metastasis. Intensive research efforts during the last several decades have increased our understanding of carcinogenesis and have identified a genetic basis for the multi-step process of cancer development. Recognition and understating of the prevalent applicability of cancer cell characterization will increasingly affect the development of new means to treat human cancer.
INTRODUCTION
Mechanisms of Contact Inhibition and its Evasion
The term ‘contact inhibition’ denotes two separate but carefully related processes in cell biology, proliferation contact inhibition and locomotive contact inhibition, established by fibroblasts while in connection with each other. Fibroblasts, until they come into contact with a neighboring cell, they move about the culture dish surface. It leads to the inhibition of further cell migration, and regular cells attach each other, making a collection of cells on the culture dish. Around the surface of the culture dish, standard fibroblasts travel until they meet a neighboring cell. Regular cells bind to each other, and further cell migration is inhibited [1].
The elementary property (Contact inhibition of Proliferation (CIP)), by which cells stop to multiply and differentiate as allotted space is filled at the confluence point. CIP is upturned under conditions including augmented cell growth and proliferation, such as healing wounds or tissue regeneration and development of the embryo. However, CIP is absent in cancer cells, and the absence of this factor leads to tumorigenesis [2].
CIP is a regulatory process that helps prevent cells from expanding into a single cell layer of thickness. If the usable substrate space in the cell is more, it duplicates easily and travels liberally. This process will last until the cells surmount the entire substratum. Regular cells would avoid replicating at this stage. When motile cells come across the confluent cultures, they display diminished mitotic activity and mobility over time. Further, though mitotic inhibition occurs later, the ascending growth occurs between colonies in contact for several days. This delay between cell interaction and the initiation of inhibition of proliferation decreases as the culture becomes more mingled. Therefore, cell-cell contact is a necessary prerequisite for preventing the spread of contact but for mitotic inhibition, it is inadequate. In addition to interaction with further cells, under the restrictions and mechanical tension exerted by neighboring cells, the cell area of the contact-inhibited cell, reduces. Mechanical stress has also been proposed to serve as an inhibitory indication for mitosis. Also, mitotic inhibition is a spatial phenomenon that happens among a small number of cells in a potentially diverse population [3].
Unchanged human cells display natural cell activity and mediate their development and spread through interactions between signaling of growth factor, cell density and environmental nutrients. As cell density rises and uniform culture is formed, cell cycle arrest is activated, and mitogen signaling pathways are regulated independently of cell metabolism or external factors. This effect is known as CIP and is important for the suitable development of the embryo as well as for differentiation, morphogenesis and tissue recovery; CIP is one of the main deregulation mechanisms in transformed cells during tumorigenesis. Many cancer cells are unaffected by confluence-tempted proliferation. Several theories were suggested to clarify the beginning of contact-reliant development arrest, like the discharge of inhibitory composites, the part of cell form on nutritional fatigue or growth aspects or growth or in the culture medium. This results in the migration of adjacent tissues, their metastases to adjacent organs, and ultimately tumorigenesis [1].
Cell-cell interactions influence intracellular signaling trails, such as ERK and Akt, and cell cycle growth is inhibited. To receptors that ease cell bonds, such as E/VE-Cadherin, growth factor receptors, interact themselves. Also, by automatically bonding adjacent cells and disturbing the spreading of traction powers, cadherins avoid interaction in multicellular clusters. Family proteins of ERM, Atypical Cadherin, Fat and Merlin, are also a part of the Hippo pathway that has developed as unique key regulators for the determination of organ size in both mammalian systems and drosophila, and contact inhibition. The lack of immunity related to malignant cell contact suppression will be affected by a reduction in the bond between the disk surface and malignant cells. Also, it could be from a rise in adhesion amid the regular and malignant cells, representing the vitro substitute as contact inhibition to the method to keep normal tissue homeostasis in vivo. When faced with normal cells, the movement of malignant cells in a given direction is not inhibited. The passage of regular cells, on the other hand, is obstructed when it is met by cells of malignancy. The cells are more rounded and extended than the malignant ones, which are spindle-made. Rounding of the cell is perhaps the index of the cell absence of adhesion to the substrate. Gene activation is caused by Cell-cell contact [1].
Recently, the NF2 gene product has been recognized by Merlin that it is involved in the suppression of the binding of adhesion molecules to the tyrosine kinase transmembrane receptor. The adhesivity of Merlin improves Cadherin-linked cell-to-cell bonding, and by recapturing receptors of growth factors, its ability to produce mitogenic signals is condensed. The other way of inhibition includes the epithelial polarity protein (LKB1), which escapes the mitogenic properties of enhanced Myc oncogene in ordered epithelial structures; on the other side, when expression LKB1 is inhibited, epithelial reliability is weakened, leading to Myc-induced renovation.
Cell adhesion affects a variety of cell behaviors by providing a wide range of mechanical and biochemical signals for cells. The Hippo-YAP pathway, which is primarily responsible for hindering cell formation in mammals, is one such pathway. Mainly, this pathway consists of a phosphorylation cascade, which is serine kinases-based and controlled by regulatory proteins that regulate cell growth by attributing to growth-control genes. However, that contact inhibited cells experience cell cycle arrest, but do not become senescent. It has now been shown that contact-inhibited (CI) cells, when substituted in a less confluent culture, restore natural proliferation and mitogen signaling. CIP can therefore be seen as a reversible mode of cell cycle arrest [4].
In addition, the cells of CI must arouse growth-activating paths such as mTOR to move to senescence from cell cycle arrest. The adhesion formations activate mechanisms that control mitogen signaling and cell proliferation until cells in cultures of high-density converge adequate such that the cell area decreases below a critical value. Therefore, the mTOR pathway of growth-promotion is blocked, and the CI cells do not change from cell cycle arrest to senescence. In cancer therapy, this has important implications; while cancer cells are not CI, their senescence machinery is still suppressed by convergent cancer cell cultures [5].
MALIGNANCY SUPPORTED BY THE DEFECTS OF THE TGF-β PATHWAY
The transforming growth factor (TGF) pathway is a key participant in metazoan biology, and its disruption can lead to tumor formation. TGF-β evolved to control neural tissue, epithelial processes, the immune system, and the healing of wounds. Tumorigenesis is related to these critical regulatory roles of TGF-β. Virtually all forms of human cells are TGF-β sensitive. By controlling not only cellular differentiation proliferation, adhesion and survival, but also the cellular microenvironment. The incipient tumors are prevented by TGF-β from moving to malignancy by preserving tissue homeostasis. However, cancer cells can possibly resist the TGF-β pathway's oppressive effect as genetically dysfunctional entities. Abnormal types of TGF-β signaling ease immune surveillance evasion, tumor growth invasion, and metastasis and dissemination of cancer cells [6-8]. The risk factor for colorectal neoplasia can also be serum TNF-β since it is linked with many recognized risk factors such as smoking, adiposity, age, and an augmented occurrence of colorectal adenomas (Table 2.1).
The inhibitory effects of TGF-β can be circumvented by malignant cells either by inactivating the main mechanism of the pathway, either by TGF-β receptors, or by changes that restrict specific ways of tumor-suppression. If the above form of bypassing is used, tumor cells can freely take advantage of the lasting TGF-β regulatory functions, acquire invasion ability, generate autocrine mitogens, or discharge premetastatic cytokines. Through receptor inactivation, decapitation of the TGF-β pathway will remove tumor inhibition, whereas amputation of the path that involves the growth-suppressive arm, not only eliminates growth suppression, but also makes additional tumor progression probability. The importance of TGF-β on the tumor stroma is also important, for the growth of cancer; TGF-β is a vital executor of tolerance of immune power and protects from immune surveillance by tumors that contain this cytokine in high levels. Faulty TGF-β responsiveness in immune cells, on the other hand, may result in chronic inflammation and the development of a pro-tumorigenic environment. Tumor-based TGF-β may utilize osteoclasts and myofibroblasts [6, 9].
For the entire TGF-β family, the receptor system is provided by five receptors of type II and seven receptors of type I paired in various mixtures. In the cytoplasmic area of these receptors, there is a serine/threonine kinase field. A switch for kinase activation is given by a small segment N-terminal only to the type I receptors kinase domain. The lively kinase core in the fundamental state is pushed against by the GS domain, repressing catalytic competence. The GS domain will be switched from the repressor portion to the substrate Smad protein-docking site by ligand-based phosphorylation by the receptors of the type II category. Only TΒRII can bind to TGF-β. In addition, TΒRI can be unified into this TΒRII-TGF-Β (Fig. 2.1) [6, 10].
The inactivation of Bi-allelic TGF-βRII happens in gastric, colon, biliary, respiratory, esophageal, ovarian, and head and neck carcinomas through the mutational changes that shorten the receptor protein or deactivate its kinase area. In tumors with microsatellite variability, TGF-βRII mutations are highly represented through a genetic disease initiated by mutations in replication healing genes. A polyadenine repeat with 10-base in the TGF-βRII coding region, susceptible to replication errors, is found. In microsatellite instability tumors, these poly (A) mistakes remain unrepaired, causing in mutant TGF-βRII alleles that encrypt receptors that are inactive. This TGF-βRII mutation style is commonly seen when the second TGFβRII allele is inactivated. In most biliary and gastrointestinal carcinomas with dysfunction in microsatellite and lung adenocarcinomas and gliomas, TGF-βRII mutations in the poly (A) tract accumulate. These mutations are available in patients of colon cancer with hereditary faults in improper repair genes. Remarkably, endometrial tumors and breast tumors do not add TGF-βRII mutations with microsatellite instability. Unstable Colon tumors in microsatellite mutations in TGF-βRII, and biallelic mutations in type II receptor of poly (A) area occur, representing that ACVR2 also has importance in tumor suppression [6].
Fig. (2.1)) TGF- transmits signals over both non-Smad and Smad pathways. TGF attaches to TRII, which, after phosphorylation of TRI and stimulate Smad2 and Smad3 in the Smad pathway (left) (Smads).Other mutations, such as missense and frameshift, are found in the TGF-βRI coding area in subdivisions of neck and head, ovarian and esophageal cancers. A specific TGFBRI*6A which is a hypomorphic allele in some types of cancer, is linked with amplified risk [11]. At the epigenetic stage, receptor alterations may also occur. Reduced appearance of TGF-βRI or TGFβRII happens in bladder, prostate, gastric and lung cancers. The defect in gastric cancers is associated with the methylation of the promoter of TGF-βRI. Finally, in Juvenile Polyposis Syndrome (JPS), which is predisposed to gastrointestinal polyps and cancer, mutations of type I BMP receptor occur [6].
Sustained discharge of TGF-β may be necessary for the maintenance of homeostasis in normal, unstressed tissue. However, TGF-β can be abundantly produced by various stromal components and blood platelets under tissue damage to inhibit inflammation and runaway regenerative cell proliferation. Truly, TGF-β also exists in the microenvironment of tumors, originally as a sign to hinder the development of pre-malignancy, but finally used by malignant cells for their self-benefit. Many tumor types have reported the existence of TGF-β demonstrating that this cancer is mostly associated with cytokine [12]. The three different tumor bases of TGF-β involve the the cancer cells as well as different tumor stroma cells, with each basis contributing to purposeful effects that depend on the context. Myeloid precursor cells, macrophages, bone marrow-derived mesenchymal, leukocytes, and endothelial cells intrude the tumors. The incidence of tumor-infiltrating cells relates to the discharge of TGF-β and, therefore a mistrusted source of TGF-β build-up at the tumor-invasion front [13]. The presence of TGF-β at this site is linked with the progression of tumors in metastasis; TGF-β of specialized local sources is also significant. TGF-β is stored by the bone matrix, which, during osteolytic metastasis, is organized [14].
Latent TGF-β activation involving many enzymatic and non-enzymatic actions is expected to differ in different tumors. With rising clinical evidence that TGF-B works as a tumor-centered immunosuppressor and stimulates tumor mitogens, which controls carcinoma invasion and a cause for the production of prometastatic cytokine, there is growing interest in TGF-B as a treatment area. Despite the sobering concerns, the pleiotropic cytokine path, compounds of anti-TGF-β, have been recognized, proving effectiveness in animal studies and clinical studies of these compounds that are in development [15].
The inhibitors of the TGF-β pathway established to date include many groups. These include TGF-β growth inhibitors hosted into immune cells or tumors. They also contain receptor-ligand interaction inhibitors like anti-receptor antibodies, antibodies of anti-TGF-β, TGF-β receptor kinases aimed by small-molecule inhibitors, and ectodomain proteins of the TGF-β duping receptor. Members of both collections of inhibitors have reached at clinical trial phase for effectiveness against cancers (breast, glioma cancer, melanoma) and alongside fibrosis, scarring, and other disorders arising from the unwarranted activity of TGF-β.
In melanoma, renal cell carcinoma and glioma tumors, therapeutic targeting of the pathway of TGF-β is focused on the basis that TGF-β employs significant properties of immunosuppression in these tumors. By blocking the TGF-β action, could also empower the immunity against the tumor. Additional tumor-specific advantages may also be available to block TGF-β action. Inhibition of TGF-β in gliomas, for instance, may decrease the development of autocrine survival issues, such as PDGF-β. Contrarily, hindering TGF-Β in ER cancer of the breast can prevent the seeding and reseed metastases by primary or metastatic tumors.
Finally, blocking TGF-β in osteolytic bone metastasis could disrupt the cycle of osteoclastogenic factors induced by TGF-β and halt tumor development. While these cases illustrate the main importance of the pathway as a mark for therapeutics, negative effects are also likely. Suppression of TGF-βmay result in autoimmune and inflammatory responses, though this has not yet occurred in systemic TGF-β blockers in preclinical or clinical trials. Inhibition of TGF-β receptor activity by other Smad pathway activators can also direct to runaway compensatory tools, comparable to what happens in individuals with deactivating TGF-βRI or TGF-βIII mutations [16]. Lastly, TGF-β signaling inhibition may boost the development of lesions of premalignancy. This will be a minor pain in cancer patients whose malignancies thrive on vTGF-β.
To determine the possibility of TGF-β based therapy, improvement in mechanisms and protumorigenic effects of TGF-β in many tumor types and in various stages of cancer progression is important. The recent development of prognostic tools for TGF-β gene expression and biomarkers for TGF-Β response can offer a way to choose patients for the intervention of anti-TGF-β in assessing the successful pharmacological targeting of this path. In experimental models and human models, a study of the TGF-β signaling pathway has provided much-needed clarification about the significance of TGF-β in human cancer and clinical compliance.
Tumor Cell Survival and Death mediates Autophagy
For programmed cell death (PCD), multicellular organisms rely on multiple types to kill damaged or unwanted cells. PCD is an evolutionary process, and apoptosis is the best-studied type of PCD. However, several cancers are unaffected to apoptosis that are alternate, non-apoptotic types of PCD, and some may be active therapeutic avenues, particularly for apoptosis-refractory cancer treatment. The apoptosis-independent cell death process is the result of autophagy over- activation, a response that normally acts as a mechanism based on quality-control [17]. The word “autophagy” was named by Christian de Duve, the Nobel Laureate, during the Symposium of Ciba Foundation on Lysosomes, held in London from February 12 to 14, 1963.
Autophagy is an intracellular degradation mechanism that takes place under many stressful conditions, including organ damage, metabolic stress, abnormal protein presence, and lack of nutrients [18
