Molecular Targets and Cancer Therapeutics (Part 2) E-Book
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- Herausgeber: Bentham Science Publishers
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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 second part of this book discusses specialized topics in clinical oncology which include the pathophysiology of various types of cancer, cancer screening, different types of cancer surgery, cancer stem cell-targeted immunotherapy, nanotechnology for precision medicine applications in cancer and cancer surveillance.
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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Veröffentlichungsjahr: 2009
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PREFACE
Cancer is a complex disease that affects all anatomical sites in the human body, causing a significant global health burden since it is considered the second leading cause of death worldwide. Recent advances in science and technology have improved the understanding of cancer evolution to discover new effective therapies. This book provides a state-of-art review of advances in cancer, including a broad overview of cancer classifications, surveillance, diagnosis and cancer treatment with a focus on innovative therapeutic approaches, such as immunotherapy, vaccines, nanomedicine, and precision medicine, in addition to cancer’s surveillance.
DEDICATION
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
Cancer Types
Amal F. Alshammary1,*,#,Mashael Al-Toub1,*,#,Maha F. Almutairi2,Mohammed Bakar3,Haifa F. Alshammary4,Arwa F.Q.B. Alanazi5,Amani F.Q.B. Alanazi6,Norah A. Alturki1,Haifa Alhawas7,Asma Alanazi7Abstract
Normally, to replace damaged cells or for the purpose of growth, healthy cells can divide according to the proliferation potency, in a systematic and controlled manner. When this mechanism is interfered with in such a way that the cell multiplies beyond the control system, a neoplasm may originate. The name (neoplasm) comes from the ancient Greek words neo, which means “new,” and plasma, which means “creation, formation.”. Even after the underlying trigger is removed, a neoplasm's growth is disorganized with that of the healthy surrounding tissue, and it continues to grow abnormally. When this abnormal neoplastic growth creates a mass, it is referred to as a ” tumor”. There are four primary types of neoplasms (tumor): benign (non-cancerous), in situ, malignant (cancerous), and neoplasms of unclear or unidentified behaviour, which follow the pattern of cell development. Oncology is concerned with malignant neoplasms, which are commonly known as malignancies or cancers. In Oncology, many cancer classifications emerged, however, the most notable of which is based on the nomenclature by the type of tissue from which it arises, or by the primary site in the body where it originally appeared. Herein, this chapter will go over the definition of cancer, classifications as well as the key differences between the types of cancers. This chapter will also cover the pathophysiology and epidemiology of the many types of cancers.
INTRODUCTION
Cancer is a prominent cause of death across the globe, as each year has caused millions of deaths on a global scale. The threatening nature of the diseases has a significant impact across the social, health, and economic burdens, amongst all other diseases. While it is not the main cause of mortality in all countries, it exerts a significant burden to be among the top five leading causes of death. Globally, WHO (2021) reports that cancer killed at least ten million people in 2020 and was the leading cause of death. Cancer is of many types, and many of them are yet to have a significantly established cause and cure. This chapter will examine the understanding of cancer so far and explore established classifications based on their origin.
Definition
Cancer is a general term used to refer to hundreds of diseases that occur anywhere in the body as a result of abnormal cell growth [1]. The abnormalities result from numerous factors and arise from different body parts; leading to a classification system to allow ease of identification. Cancer cells are also known as malignant cells, depending on the course of their progression. Cancer development has numerous risk factors that could lead to the abnormal growth of cells. Many factors have been put forward, including environmental or personal factors. These include certain viruses such as the Human Papilloma Virus, radiation, certain chemical compounds, genetics, dietary problems, age, stress, hormones such as estrogen, and many others [2].
The onset of cancer is marked with signs and symptoms like any other disease, which are reliant on the type of cancer. The location, for example, can be a determining factor in what symptoms would be felt first. For example, cancer located in the brain regions could have major symptoms of seizures, while for breast cancer, lumps on the breast could be felt. However, in some forms of cancer, the symptoms often do not appear until it is too late [3]. However, some general signs and symptoms are recommended to follow up on in case they occur, including but not limited to loss of appetite and weight for no reason, persistence in nausea and fatigue, increasing pain in parts that were not so before, and recurrent infections without reason.
Cancer development is not straightforward, and the presence of a carcinogen does not always imply it will develop. A series of complex processes and procedures are always inhibited at every stage through the body's defence mechanisms. However, upon failure of these mechanisms, cancer will develop through a series of changes that allow the carcinogens of agents in the body to produce factors that promote tumor growth. These carcinogens often target the cells at the DNA level to destroy or reduce the function of these cells to carry out their expected roles and thus, over time, render the cell a good site to start developing uncontrollable growth. Sometimes these cells escape and move from their initial site to neighbouring cells and cause further damage to these news cells, thus causing significant spread.
Nomenclature
Cancers are classified into numerous categories, as mentioned depending on the site or origin or the cause. The classification into the correct types through naming is known as nomenclature. According to Singer et al., the process is critical for various reasons, including ensuring a correct diagnosis [4]. Discovering the right type of cancer means that the response would be highly specific since different types of cancers have their own responses and therapeutics that would be best for the patient at that given time. For example, breast cancer might be treated differently from brain cancer due to the location of the tumors. Since cancers are not fully understood, researchers are still building profiles and uncovering new information about the different types of cancers that occur in people. Therefore, having the right naming system can help researchers further understand what they are dealing with. It has also been shown that correct naming and identification of cancer allows oncologists to inform the patient more clearly on the progression of the disease, the aetiology, and expectations. Most importantly, the different types of cancers are now being studied using far more advanced methods, such as biomarker studies that have identified specific genes and molecules within the body that could be targeted far more precisely compared to if randomised studies were used. A good example is the identification of the HER2+ gene; a growth factor that impacts women to cause aggressive breast cancer and has a high fatality rate. By correctly identifying whether women with breast cancer are positive for the gene, they can be treated with advanced medication specifically made for the gene, and their progress tracked using biomarker studies, thus increasing the chances of quickly identifying what works and what works does not. This is because, as mentioned, there are hundreds of cancers and not all are well understood. Therefore, nomenclature becomes essential.
As cancer is a collection of diseases rather than a single disease, arising from different parts, the nomenclature is based on the origin of the cell as well as the possible cause. This is so because the biological properties in the cells provide a common origin or shared characteristics. As the cancer cells develop, they involve numerous tissues, carcinogens, and mechanisms, thus, tracking it based on where it affects has been seen as not ideal to some degree. One of the most common nomenclatures used is that classification according to whether they are benign or malignant [1]. The classification into benign or malignant has been found to be significantly useful because there are implications on the biological mechanisms of how these tumors operate, as well as in examining what challenges could arise at the clinical stage [5]. Benign neoplasms or benign tumors are cancers capable of proliferating the cell abnormally, resulting into a swollen mass. On the other hand, malignant is mainly distinguishable from benign tumors because of the ability to move out of a cell and invade the surrounding cells to cause further cancerous spread [6]. Malignant cells are, therefore, capable of causing further harm when the disease progresses. According to Nurmik et al., they can be classified further into subdivisions that include, for example, hematopoietic or solid tumors, sporadic and hereditary neoplasms, or even adult and child-affecting cancers [2]. Both benign and malignant tumors have certain similar characteristics based on shared cell structures as well as significant differences. These are discussed in detail in the next section.
CHARACTERISTICS OF BENIGN AND MALIGNANT TUMOURS
Tumours, whether benign or malignant, share many characteristics based on aspects, such as a common origin and shared neoplasm. However, distinguishing characteristics are more vital to patient treatment. Experts observe the pattern of development of the tumor, the characteristics of the tumor from the cell origin, and the possible pattern of growth to make a clinical judgment. These characteristics, as mentioned, tend to determine how the disease will be handled.
The common features for both benign and malignant tumors contain a shared stroma from the host cell. The stroma is a significant factor in this case because it contains tissue, blood vessels, and other cells that tumors utilize in their growth. Therefore, tumor progression for both types is supported by the continued exchange of nutrients and oxygen through the stroma. Another shared characteristic is the parenchyma, which has been shown to possess the ability to determine the behavior of the tumor in subsequent stages. The parenchyma is supported by neoplastic cells that will form parenchyma and eventual clinical progression. The parenchyma also plays a role in the naming of the tumors.
The most distinguishing factor between benign and malignant is that benign tumors tend to have a localized effect, while malignant tumors can spread to invade both the neighboring cells as well as cells in other areas [4]. For benign tumors, there is a less aggressive stance associated with them since the effect is contained and not invading nearly cells. However, while these types of tumors are less aggressive, they are not without significant effect on a patient; and could cause problems to the cell itself, the surrounding blood vessels as well as nerves. The size of the tumor will determine its local effect within the cells and on the nerves or blood vessels. More importantly, the location of some benign tumors is more complex and damaging than others, especially if near vital organs and tissues [7].
Depending on where they originate, benign tumors are given the suffix -oma to distinguish them from others. For example, when the benign tumor affects fibrous tissues, this will be known as fibroma, while that originates from blood vessels, for example, will be known as hemangioma. Further classification takes into account the microscopic patterns as well. Therefore, when a tumor causes the surface of where it grows to form finger-like fronds that are microscopic, this will be known as a papilloma [8]. On the other hand, malignant tumors display different characteristics related to the growth pattern in that the cell can escape into neighbouring and far-site cells to cause further harm and invasion. Malignant tumors are aggressive because of their ability to metastasize in close and far cells. In malignant tumors, the cancers cause a significantly higher degree of damage to the patient due to, firstly, the burden of aggressively spreading around or all over the body. However, the primary tumor determines the extent of the damage as well based on its location, size, and effects of expansion on the other sites. Certain sites are considered more prevalent in the malignant tumor spread, such as the brain, bones, lungs and liver [9].
There are three ways in which malign tumors spread, one of which is a direct invasion. This occurs mostly when there is a direct escape from a cell and making contact with the neighbouring cells that also become infected. Malignant cell tumors can potentially spread to other parts of the body via the lymphatic system. These types of cancers are known as lymphomas, given that their main source of spread is connected to the lymphatic system. Finally, the malignant cells can also utilize the blood to form leukemia. These cancers are thus known as hematomas since they use the hematogenous system to spread [7]. In the tissues and organs most affected, like the liver and the lungs, fatalities occur due to the rapid replication of the tumor cells to replace the functional parts of the cells within these organs. Eventually, nodes large enough form in the form of metastases that replace the tissue or organ and lead to eventual organ failure [3].
The nomenclature for the malignant tumors also follows that of the benign tumors where the origin is critical. These can thus result in sarcomas and carcinomas, for example, which represent cancers originating from mesenchymal cells or epithelial lining cells, respectively. These groups can be further subdivided into smaller categories that include fibrosarcoma, which could have originated from the fibrous tissue. This means that the source origin and area affected are both taken into account as cancer progresses. Important distinguishing characteristics of the malignant cells cannot be without understanding the distinguishing features that make them aggressive. These types of tumors have been termed as having features like genome instability that help to cause mutations. These mutations make it harder for the immune system to recognize and fight against. Furthermore, malignant tumors also contain inflammation features that are capable of promoting tumor growth [5]. Conway, Purkayasth & Chestnutt found that due to such features, malignant cells become better at evading immune destruction and thus causing tumor escape, or breaking down the existing cellular mechanisms that make it possible for a cell to function normally in areas such as the immune system deployment among other basic functions [1].
Hanahan & Weinberg examined and explained in detail the distinguishing features of malignant cancers and termed them hallmarks of cancer. In the analogy, at least six major distinguishing features were established that made malignant tumors stand out [10]. The first was the ability to evade tumor growth suppressors. The tumor growth suppressors are gens tasked with ensuring the natural progression of cells towards cell death when that cells are not aligned to proper development. The suppressor cells also act as messengers to correct mistakes in the DNA processes to enable proper functions of the cells, especially in the growth of new cells. Evading genes like TP53 are thus one of the characteristics that allow malignant cells to thrive. Another hallmark mentioned by Hanahan & Weinberg (2011) relates to the fact that malignant cells allow proliferation to occur continuously [10]. Malignant cells are also known to allow an environment of replication to persist, resist the death of cells, induce angiogenesis and eventually invade neighbouring and far cells.
CLASSIFICATION
Carcinoma
The human body is made up of trillions of living cells that divide, grow, and wear out in a highly controlled way that is controlled by DNA. The cells in a baby or fetus multiply faster to allow them to grow, but in adults, cells only divide to substitute the damaged ones, the dying or repairing injuries. Cancer occurs when some genes mutate, like DNA. Mutation of genes can negatively affect the proper growth and division of cells. Exposure to radiation, viruses or smoking can cause these mutations; consequently, new abnormal cells are formed [11]. It is an abnormal growth of a tissue that is very harmful, originating from the epithelial or cancer can be external or on an internal body lining. Carcinomas represent 80 to 90% of all cancer incidences [12]. Epithelial tissues are found in every part of the body. They can be found in the skin; they even cover organ linings and internal passageways like the gastro-intestinal tract. Carcinomas are categorized into two groups: Squamous cell carcinoma, which arises from the squamous epithelium, and adeno-carcinoma, which forms on an organ or gland.
Squamous cell carcinoma represents most nonmelanoma skin cancer related to metastatic disease and fatalities. Early disease detection and treatment are key to preventing neoplastic progression. Diagnosis can either be by histopathology or surgical excision, but with the growth of technology, there are diagnostic imaging techniques like dermoscopy and reflectance confocal microscopy increasing the accuracy of diagnosis, and they are non-invasive [13]. Adenocarcinomas mostly occur in mucus membranes because they initially appear as a thick plague of white mucus. They freely spread in the soft tissue areas they affect. The squamous carcinomas cells affect many parts of the body. Most carcinomas affect organs or glands that have secretion power, like the breasts responsible for producing milk, the lungs, colon, prostate, or bladder.
Lung Cancer
Epidemiology
Nowadays and worldwide, Cancer is one of the leading causes of death and a significant impediment to rising life expectancy. In 2020, an approximately 19.3 million new cancer cases (without non-melanoma skin cancer, 18.1 million) were reported worldwide, with almost 10.0 million cancer deaths (without non-melanoma skin cancer, 9.9 million) [14]. Merely due to population growth and ageing, the global burden of cancer is projected to rise to 27.5 million new cases and 16.3 million cancer deaths by 2040 [15].
Over the last several years, lung cancer has become the most prevalent diagnosed cancer type. Hence in 2020, the second most prevalent type of cancer is lung cancer. A total of 2.2 million new lung cancer cases were recorded for both sexes combined, accounting for 11.4% of the global cancer burden. With about 1.8 cancer deaths (accounting for 18.0% of total cancer deaths), lung cancer is considered as the leading cause of cancer-related death [14]. Separately, in males, lung cancer continues to be a prevalent cancer diagnosis, with an estimated 1.4 million diagnoses in 2020, and the highest mortality rate (1.2 million cancer deaths). While in females, it ranks third in terms of incidence (0.8 million new cases), after breast and colorectal cancer, and second in terms of mortality (0.6 million deaths), after breast cancer (Fig. 1.1). On the whole, males have about double the incidence and mortality rates comparing females, though also, the male-to-female ratio varies greatly across regions [14].
Fig. (1.1)) Age-standardized rates (ASR) for cancer incidence and deaths for each gender worldwide. (a) Age-standardized incidence rates for cancer, in males using data from GLOBOCAN, 2020. (b) Age-standardized incidence rates for cancer, in females. (c) Age-standardized deaths for cancer, in males. (d) Age-standardized for deaths from cancer, in females. Data source: GLOBOCAN 2020. Graph production: created by us by using the free-to-use IARC (http://gco.iarc.fr/today), World Health Organization [14].Furthermore, in regard to the geographic patterns of lung cancer, females have different geographic patterns in incidence rates than males, which can be due to historical disparities in cigarette smoking (Fig. 1.2) [16]. In males, Polynesia, Micronesia, Central and Eastern Europe, and Eastern Asia have the highest incidence rates of lung cancer, with Age-standardized rates (ASR) of 53.0, 51.3,49.0, and 48.1 per 100,000, respectively. On the other hand, in females, Northern America (30.1 per 100,000), Northern Europe (26.8 per 100,000), and Western Europe (25.0 per 100,000) were reported to have the highest incidence rates (Fig. 1.3) [14].
Risk Factors
Tobacco smoking is, without a doubt, the most significant and predominant lung cancer risk factor. One of the first pathological conditions to be linked to cigarette smoking was lung cancer, and it was a rare condition at the turn of the twentieth century [17]. There are over 7,000 chemicals in Tobacco smoke; out of these chemicals, at least 69 known carcinogens, in addition to several toxicants that are linked to serious illnesses [18]. In smokers, lung cancer incidence is approximately proportional to the dose rate (number of cigarettes per day), but it increases even more rapidly with smoking length [19]. Even so, there are also a significant number of lung cancer patients who have never smoked [20]. In both smokers and non-smokers, age is a significant predictor of lung cancer [21]. In non-smokers cases, there are other putative risk factors, such as cooking fumes, environmental tobacco smoke, occupational, inherited genetic susceptibility, environmental exposures to carcinogens, pre-existing lung disease (e.g., history of chronic obstructive pulmonary disease (COPD), which comprises chronic bronchitis and emphysema), hormonal factors, and oncogenic viruses [20].
Pathophysiology
Lung cancer is a rapidly metastasizing and highly invasive type of cancer that can arise from different types of cells. The latest World Health Organization (WHO) classification of lung tumours, (2015) 4th edition of the “WHO classification of tumours of the Lung, Pleura, Thymus and Heart”, recognizes lung cancer as a category of heterogeneous tumours with many differentiation forms [22]. In addition to the histological and cellular characterization, the importance of molecular or genetic characterization of lung cancer is recognized in this classification [22]. Conventionally, lung cancer has two main types: Small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC), which develop and spread differently. Lung cancers have a lot of histological heterogeneity, so this classification takes that into account [23].
Fig. (1.2)) Geographical distribution. Age-standardized rates (ASR) for cancer incidence for each type of cancer worldwide. (a) Age-standardized incidence rates for cancer, in both sexes using data from GLOBOCAN, 2020. (b) Age-standardized incidence rates for cancer, in males. (c) Age-standardized incidence rates for cancer, in females. Data source: GLOBOCAN 2020. Graph production: created by us by using the free-to-use IARC (http://gco.iarc.fr/today), World Health Organization [14]. Fig. (1.3)) Geographical patterns of lung cancer. Age-standardized rates (ASR) for cancer incidencefor each type region. shows age-standardized incidence rates for cancer, in both sexes using data from GLOBOCAN, 2020. Data source: GLOBOCAN 2020. Graph production: created by us by using the free-to use IARC (http://gco.iarc.fr/today), World Health Organization [14].Accordingly, without an immune-histochemical profile to achieve differentiation as well as classify genetic alterations and biomarkers, some of which have predictive value for therapy decisions, NSCLC reporting is not permissible [22]. The new WHO classification of lung tumours distinguishes between various types of lung cancers, including adenocarcinomas, squamous cell carcinoma, neuroendocrine tumors, large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, and a number of other types (Table 1.1). This wide range of histopathologic diagnoses that indicates tumor heterogeneity, may be clarified by a variety of origin cells or differentiation pathways [23].
To efficiently select tumors for targeted molecular testing, special emphasis is put on distinguishing adenocarcinomas from other lung cancers in cytology specimens or small biopsies. Adenocarcinomas are further categorized in resection specimens based on the structural patterns to distinguish tissue types with prognostic importance. On the basis of a number of characteristics, including tumor cell proliferation rate, neuroendocrine tumors are classified as carcinoid tumours (typical carcinoid and atypical carcinoid), small cell carcinoma, and large cell neuroendocrine carcinoma [16, 24]. Furthermore, as a result of advancements in genomic characterization, lung cancers are now defined and classified by tumor biomarkers and genetic alterations, such as mutations, gene expression, rearrangements, and amplifications (Table 1.2), that are important for tumor growth and survival and can be targeted with specific drugs or immune checkpoint blockades, thanks to advances in genomic profiling [25].
Breast Cancer
Epidemiology
Breast cancer is the most common form of cancer worldwide. In 2020, the estimated number of new breast cancer cases was about 2.3 million, representing 11.7% of the global cancer burden. Globally, it ranks as the first prevalent type of cancer. However, breast cancer is responsible for a total of 0.7 million cancer-related deaths, which account for 6.9 percent of the total cancer deaths. So, breast cancer becomes fifth among the cancer types that lead to death after the lung, colorectal, liver, and stomach cancers (Fig. 1.1). In females, breast cancer is the most common malignancy that leads to death. worldwide, with a total of 0.68 million (15.5%) cancer-related deaths. Certainly, it is also the leading type of cancer among females worldwide (with an estimated number of new breast cancer cases of 2.26 million, account of 24.5 percent of the global cancer burden) (Fig. 1.1) [14].
Geographically, the females population in Australia and New Zealand (ASR of 95.5 per 100,000), Western Europe (ASR of 90.7 per 100,000), and Northern America (ASR of 89.4 per 100,000) have the highest incidence rates of breast cancer. At the same time, the highest mortality rates due to breast cancer are found among the females population in Melanesia (ASR of 27.5 per 100,000), Polynesia and Western Africa (ASR of 22.3 per 100,000), and Caribbean (ASR of 18.9 per 100,000) (Table 1.3) [14].
Risk Factors
Several factors can be associated with a higher risk of breast cancer. For instance, the hormonal status. Hence the breast is an organ that reacts to estrogen, high levels of the estrogen hormone, such as in the case of women who take estrogen replacement therapy or birth control pills report that their breasts become swollen and tender as a result of the drug [26]. Besides, Breast cancer affects more single women than married women [27, 28]. In addition to that, aging, family history, reproductive factors (e.g., late menopause, early menarche, late age at first pregnancy and/or low parity), lifestyle (e.g., drinking too much alcohol and/or eating too much fat), genetic factors (e.g., abnormal amplification or mutations in oncogenes and anti-oncogenes) can increase the breast cancer risk [29].
The breast is an interconnected tubule-alveolar organ that is held together by an uneven connective tissue that is present in both genders (males and females) of human beings. Mammary glands originate from a modification of sweat glands. The lining mammary epithelial has three types of progenitor cells: luminal-restricted progenitor, bipotent progenitor, and myoepithelial-restricted progenitor cells [30]. Typically, breast tumors begin as ductal hyperproliferation and progress to benign tumors or even metastatic carcinomas as a result of continuous stimulation by carcinogenic factors. Breast cancer induction and development are influenced by tumor microenvironments such as stromal factors and macrophages [29]. The malignant breast tumour or breast cancer is a complicated disease with significant inter- and intra- (genetic and epigenetic heterogeneity) tumor heterogeneity [31-33].
Pathophysiology
Breast carcinoma is a set of biologically distinct objects with specific pathological characteristics and clinical consequences [34-36]. According to growing evidence, breast cancers with different histopathological and biological characteristics have distinctive patterns that contribute to different treatment responses and should be treated differently [37]. Breast carcinoma can be classified based on a variety of factors, including site or degree of invasion, type of tissue that the carcinoma is raised from, and the hormonal and genetic pattern exhibited by cancer [38]. Based on the invasiveness, breast carcinoma is divided into two major types: non-invasive (NIBC) and invasive breast carcinoma (IBC). NIBC, which also can be known as carcinoma in situ, is cancer that has not spread beyond the lobule or ducts in which it is located [39].
Furthermore, there are two subtypes of NIBC, which are classified according to the type of tissue, Lobular carcinoma in situ (LCIS) and Ductal carcinoma in situ (DCIS). LCIS evolves within the breast lobules [40]. This type has not spread outside the lobules into the surrounding breast tissue [41]. Likewise, DCIS is the general form of non-invasive breast carcinoma which only affects the breast duct [42]. In contrast, IBC is the type of breast cancer that occurs when the neoplastic cells from the lobules or milk ducts spread out into close vicinity to breast tissue or even metastasize to various organs of the body [43, 44]. IBC comprises many subtypes in addition to a rare breast cancer types (Table 1.4 and Fig. 1.4).
Pancreatic Cancer
Epidemiology
Pancreatic cancer has an incidence of 60430 cases in the united states, of which 52% male and 48% female population. The international incidence of the disease is 458,918 new cases which represent 2.5% of all cancers. Age-standardized incidence ranges from 7.7 per 100,000 population in Europe to 2.2 per 100,000 in Africa. Incidence rate differences were noted with a maximum fold of 30 between countries, where Hungary has the highest rate of 10.8 per 100000. Pancreatic cancer is the seventh leading cause of Global cancer deaths in developed countries and the third most common in the united states of America. Pancreatic cancer has a great magnitude of disease burden worldwide, with mortality of 432,242 deaths in 2018. Future projections of a possible increase of incidence rates by 355,317 new cases in 2040. The occurrence of disease before age 45 is rare, and the incidence reaches the peak at age 65- 69 for males and at 75 -79 for females gender and ethnicity differ in term of race. In the united states, disease occurrence is greater in males than in females and in blacks than in whites.
Fig. (1.4)) Classification of breast carcinoma. Breast carcinoma is classified based on different characteristics, including: degree of invasion, type of tissue that the carcinoma is raised from, and the hormonal and genetic pattern that exhibited by the cancer. Graph production: created by us.Pathophysiology
Cancer of the pancreas originates from the exocrine and endocrine parts of the pancreas. The most common origin of pancreatic carcinoma is the exocrine portion, representing 93% of the cases. The exocrine portion includes ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. The head and neck of the pancreas are the most common sites of carcinoma, which represent roughly 75% of cases. The second common site of carcinoma is the body of the pancreas, which represents 15-20%, whereas 5-10% occur in the tail of the pancreas.
Risk factors associated with pancreatic cancer are tobacco smoking, obesity, high alcohol consumption, history of pancreatitis, diabetes, and family history of pancreatic cancer. One of the most common, highly associated risk factors is tobacco smoking. Diabetes mellitus consider an early manifestation of pancreatic cancer. Based on the International Pancreatic Cancer Case-Control Consortium, diabetes has a causal role in pancreatic cancer. Chronic pancreatitis is one of the underlining causes of pancreatic cancer, which mainly contribute to about 5% of the cases. Another risk factor which considered as a dependent factor is excessive alcohol consumption, especially when it is associated with chronic pancreatitis.
Tobacco smoking is one of the most common environmental and behavioural risk factors of pancreatic cancer, which accounts for up to 30% of cases. There is a 2-fold higher risk for pancreatic cancer among smokers. People who smoke 40 pack-year have up to 5-fold higher risk for the disease. In smokers to reduce the risk of pancreatic cancer to those non-smokers it requires 5-10 years cessation of smoking. Further, central obesity is well established associated risk factor with pancreatic cancer. Younger age pancreatic cancer is markedly associated with obesity whereas older age and obesity are associated with poor survival. Individuals with rich fruit and vegetable diet have a lower incidence. In addition, A 5-year duration of diabetes millets will increase two-fold in the risk of pancreatic cancer. Additionally, there is a high association between pancreatic cancer, older age and sudden onset diabetes mellitus especially type 2. Patients with long-standing chronic pancreatitis have a 26-fold risk of pancreatic carcinoma. Another major risk factor that will increase the risk of pancreatic cancer by 50-fold is hereditary pancreatitis, mainly in patients older than 55 years old. Chronic pancreatitis caused by alcohol is linked to an increased risk of pancreatic cancer.
Almost 10% of patients with pancreatic cancer have a genetic predisposition. Genetic mutations are seen in pancreatic carcinoma, mainly in KRAS2, p53, and Smad4 genes, representing 80-95%, 50%, and 55%, respectively. One-third of chronic pancreatitis patients have a mutation in p16 and one-fifth have k-Ras mutations. Another gene mutation is BRCA-2 which usually runs in families. One typical pathological feature seen in pancreatic adenocarcinoma is pancreatic intraepithelial neoplasia. Initial changes to be linked to KRAS2 gene mutations and telomere shortening. p16/CDKN2A become inactive and inactivation of both TP53, MAD4/DPC4. This gene malformation is correlated with the development of dysplasia resulting in the development of ductal carcinoma of the pancreas. In earlier stages of the disease, its undiscoverable and from that time to the diagnosis leads to the accumulation of genetic malformation, which explains the complexity and chemotherapy resistance. There is a 40% cumulative risk of pancreatic carcinoma with hereditary pancreatitis. The presence of MEN-1 genetic syndrome has 50% incidence of developing symptomatic pancreatic cancer, which is responsible for disease-specific mortality. Patients with Von Hippel-Lindau syndrome are associated with developing pancreatic cancer in 17% of patients who have the syndrome. Familial atypical multiple mole melanoma increases the relative risk of pancreatic carcinoma by 13 to 22-fold. Germline malformations in brca1-2have been associated with an increase in the risk of pancreatic carcinoma by 2.3 to 3.6-fold, whereas BRCA2 is responsible for 7% incidence of pancreatic cancer.
Multiple subsets of genes go through genetic alteration which is by activation and inactivation during pancreatic cancer development. Oncogenes are activated, and tumor suppressor genes are inactivated, which causes the disease to start and progress. Additionally, in numerous cell signalling pathways, deregulation of molecules occurs, for instance, EGFR, Akt and others. The first step is by activation of oncogenes which happens by point mutation and amplification. Most of pancreatic cancer cases are found to have activation of Ras oncogene. Its activation involves in growth factor-mediated signal transduction pathways and point mutation. This point mutation leads to a constitutively active form of Ras. As a result, the active form of Ras binds to GTP and sends uncontrollable stimulation signals to downstream signalling pathways, causing uncontrolled cell proliferation. Other genes associated with activation of oncogenes with pancreatic cancer notch and cox-2. The alteration of the notch gene and its signalling is associated with carcinogenesis of the pancreas. The cox enzyme is in charge of stimulating the synthesis of prostaglandins, which leads to cell growth stimulation. Inactivation of the suppressor gene, which can be caused by mutation, deletion, or hypermethylation, is another crucial event. p16, p53, SMAD4, and PTEN are tumor suppressor genes found in pancreatic cancer [56].
Another event is the Deregulation of EGFR signalling, comprising an extracellular ligand-binding domain, a hydrophobic transmembrane region, and an intracellular tyrosine kinase domain. The binding of a ligand to EGFR stimulates receptor dimerization, resulting in intracellular transphosphorylation of tyrosine residues. Phosphorylation of EGFR activates molecules in several cells signalling pathways, including PI3K, Src, MAPK, and STAT, inducing cell cycle progression, cell division, survival, motility, invasion, and metastasis. Additionally, the Deregulation of Akt signaling is another factor associated with pancreatic carcinogenesis. The Deregulation of Akt signaling will result in the inhibition of apoptosis and activation of NF-κB [56].
Prostate Cancer
Epidemiology
The prostate gland is an important component of a man's reproductive system. Its main job is to release an alkaline solution that protects sperm as they transit through the acidic vaginal environment. This expands the sperm's lifespan, giving it more time to fertilize the egg successfully. This fluid also contains proteins and enzymes that help sperm grow and thrive. Furthermore, the prostate fluid's increased volume in comparison to the seminal fluid and sperm provides for easier mechanical propulsion via the urethra [57].
Based on 2018 case numbers, a total of more than 1.25 million cases of prostate cancer were registered worldwide, accounting for over 7% of the total cancer cases, with 13.5% of all cancer incidents in males. This makes it the second most common cancer in males [58]. Moreover, it is responsible for just under 4% of cancer-related deaths worldwide. This information is in reference to the abstract numbers of the newly diagnosed and deceased people due to this cancer which was as high as 1,280,000 and 359,000, respectively. The rate of mortality was found to be correlated with increasing age, especially in those individuals who were newly diagnosed after the age of 65 years. Those among that age group attributed to around 55% of the deceased cases [59].
Another notable fact is the disparity in incidence rates among different countries. France has been found to be the highest incidence rate, with over 189 new cases per 100,000 persons; meanwhile, on the other side of the spectrum, Bhutan (a country in Eastern Himalayas) had only 1 new case per 100,000 people. The reason behind this significant difference among nations is not entirely understood. It is suspected that extensive prostate cancer testing could be a major contributor for the ‘overdiagnosis’ of the condition in the USA and Europe by possibly being the reason for diagnosing up to 40% of the cases [59].
Risk Factors
Through extensive research on the factors that play a part in the progression of this cancer and mortality rate, it was found that following elements play a vital part in the incidence and/or mortality rates. The first is age, as increasing age has been found to be a major contributor to the risk of prostate cancer. It has been shown that the incidence of developing it significantly increases after the age of 50 years, with a risk of incidence being 1 in every 52 men for those of the age 50 to 59 years; for those aged 65 years, the risk incidence rises to 60% [60].
The second is ethnicity and environment, as men of African American ethnicity are more likely to develop prostate cancer by approximately 60% more than white men. This figure increases to double in regards to the difference in mortality rate [61]. The reason behind this disparity has not been fully explained, but it has been suggested that it could be a combination of genetic and environmental factors. Environmental factors play a role here as when compared to men in Africa, Chu et al. (2011) found that, African American men in the US had a higher incidence rate by as much as 40 times [62]. The trend also applies to Chinese men who live in the US (16-fold higher incidence rate) compared to men in China, further suggesting that environmental factors have a significant impact [63].
The third is obesity, as studies have shown that a 5 kg/m2 increase in BMI of men could increase the risk of the lethal prostate outcome – defined as diagnosis of distant metastases or death due to prostate cancer – by 15-20%. This is well more evident in patients who suffer from obesity at the time of their diagnosis. Furthermore, obesity has also been linked to the chances of prostate recurrence. This can also be linked to the lower level of testosterone which significantly decreases with the increase in body weight, that in turn increases the risk of more aggressive tumors.
The fourth element is family history and genetics. Having first-degree relatives, which are either the father or a brother, diagnosed with prostate cancer can increase the chance of it developing by up to 3 folds in that person. This risk increases even more if the onset in the first-degree relative was at an early age; also, a further risk increase can be seen if multiple first-degree relatives were diagnosed with this illness. High-penetrance level of genetic variation has been proposed to be the cause behind an estimated 10% of all prostate cancer cases. This trend of genetic variation seems to be inherited in a mendelian inheritance fashion through families. For the time being, the number of genetic mutations and the sequence of mutations involved are not fully known [64].
Fifth is diet; as with many other types of cancer, diet can be linked to the chance of developing the cancer of the prostate. Overall, mixed results were found in regard to the correlation of diet with the rate of prostate cancer. However, there is at least a small positive significant association between high-saturated-fat diets and the incidence of prostate cancer. In fact, 20 epidemiological studies have been done in relation to this type of diet, and all have shown a significant level of correlation with it [65
