Understanding Cancer: From Basics to Therapeutics

By Buddhi Prakash Jain and Shweta Pandey

Understanding Cancer: From Basics to Therapeutics presents both basic concepts and research prospects in the field of cancer biology. This book summarizes the fundamental aspects of cancer and presents a detailed description of molecular aspects as well as treatment and therapeutics for patients.

The book is divided into three parts: the first part deals with the basics of cancer, including etiology and medical diagnosis; the second part explores the molecular mechanisms associated with cancer, focusing on cell cycle and apoptosis, cell metabolism, gene regulation, epigenetics, and stem cells; and the third part is dedicated to therapeutics, discussing chemo and radiotherapies, gene, hormone, herbal, and immunotherapies.

It is a valuable resource for cancer researchers, oncologists, graduate students, and biomedical researchers who need to understand the fundamental topics related to cancer to apply to their research work or clinical setting.

• Presents fundamental aspects of cancer in a didactic way to make the content easily applicable by readers
• Illustrates the content through detailed images developed by the authors exclusively for the book to facilitate comprehension
• Summarizes the content of each chapter with several tables and schematic diagrams for quick consult

• Language: English
• Publisher: Academic Press
• Release date: Jan 13, 2022
• ISBN: 9780323983969

Book preview

Preface

Cancer is a complex disease in which cells divide in an uncontrollable manner, migrate from their site, and invade other tissues. Currently, it is a global disease and the second leading cause of death worldwide. According to cancer statistics, in 2020, approximately 10 million cancer deaths occurred globally. This book sums up the extensive research in oncology and our present understanding of the disease. The book is divided into three parts with a total of 18 chapters, covering all the current data. The first part is concerned with the basic knowledge of cancer and has four chapters dedicated to the primary knowledge of cancer, its types and etiology, and the methods that are used to diagnose it. The second part deals with the cellular and molecular mechanisms that are responsible for the occurrence of the disease and includes nine chapters dedicated to the various molecular and cellular mechanisms that are affected during the progression of cancer, as well as those whose modification results in cancer. These include cell cycle alteration, metabolism of cancer cells, the primary signaling pathways associated with cancer and their modifications, epigenetics, and the regulation of gene expression in cancer. The third part of the book emphasizes current knowledge of various therapies and treatments available. There are five chapters that give detailed accounts of chemotherapy, radiotherapy, gene therapy, and therapies based on hormones, immunoglobulins, and various plants. This book aims to cover almost every aspect of cancer. It is written in a very simple yet detailed manner so that it can be easily understood by an undergraduate as well as any research scholar. Each chapter has very detailed information and various figures in addition to tables to make the book interesting as well as easy to understand. The book endeavors to solve and clarify the basic confusion and concepts regarding cancer and its occurrence. The book will be useful for the new reader and a researcher in this field.

Chapter 1

A brief tour guide to cancer disease

Padmini Bisoyi

School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Abstract

All multicellular organisms are made up of millions of cells. Under physiological conditions, the cells usually behave in a specific biological manner to sustain a normal healthy life. However, due to the genetic alteration, once a cell has turned cancerous, it divides unanimously until a tumor mass is formed. A tumor mass may be solid or fluid-filled but is quite different from inflammatory or other swellings. Sometimes, the term tumor and cancer are used interchangeably, which can be misleading, but medical science has made it clear that all tumors are not cancerous. Broadly, tumors are classified according to their nature of growth and aggressiveness as benign (noncancerous) and malignant (cancerous) tumors. The initiation of tumor development is the same for both benign and malignant tumors, such as single-cell mutation, but the metastatic potential of tumors always raises a red flag. Seven hallmark changes in cellular physiology collectively determine the malignant phenotype. Altogether, cancer development is a multistep process that involves hyperplasia, dysplasia, carcinoma in situ, invasive carcinoma, and metastasis. Metastasis is the key process that enables cancer cells to escape and migrate from the primary tumor to other locations of the body and form a new tumor (secondary tumor). However, for growth and survival, cancer cells stimulate angiogenesis and vasculogenesis to access nutrients and oxygen supply and the removal of waste products. This chapter will provide basic information about the disease - cancer.

Keywords

Cancer; Tumor; Metastasis; Neoplasm; Angiogenesis

1.1 Overview of cancer

Cancer is the second leading cause of death after cardiovascular diseases, worldwide. The word cancer generates emotional agony among people. Public and patients often inquire, When there will be a complete cure for cancer? The answer to this simple query is very challenging, because cancer is not a single disease, rather a combination of many disorders that involve severe cellular dysregulations. Unlike few primitive animals, all the species including humans are affected by cancer. Cancer is undoubtedly a serious and potentially life-threatening illness but most often it is exaggerated and over-generalized. Once a cell has turned cancerous, it divides until a mass of cells forms a tumor. Different diagnostic tests can quickly distinguish between malignant or cancerous tumors and those that are benign or harmless. As a malignant tumor progresses, cells or clumps of cells break off and spread or metastasize, around the body via the lymphatic system and blood vessels. The only hope to control cancer is to learn more about its cause and pathogenesis and understanding cellular physiology at the molecular level.

1.1.1 Definition of cancer

Cancer may be defined as a complex disease, which is usually a combination of cellular abnormalities developed by mutation of a particular gene (Ras protein is mutated in many human cancers) or production and function of abnormal proteins.

In all types of cancer, some of the body cells undergo uncontrollable division and spread to surrounding tissues. In other words, we can say that cancer is simply the failure of cell cycle control or disease of cell division.

1.1.2 Historical highlights

Cancer is not a disease of the modern era, rather researchers in 2015 revealed that fossil records showed leukemia in Neolithic women. Moreover, signs of cancer are found in bones of mummies from Peru and ancient Egypt dating back as far as 3000 BC. An ancient Egyptian medical text The Edwin Smith Papyrus, documented eight cases of breast ulcers or tumors in Egypt that were treated with cauterization. The document, however, also states that there is no treatment for cancer. Dating back to 400 BC, Hippocrates (popularly known as the father of medicine) was the first to describe cancer and its treatment. He was also the first to use the Greek term "karkinos" or crab to describe a malignant tumor (cancer). The disease is named after crab because the network of blood vessels on a tumor, resembles as claws of a crab reaching out into the surrounding [1].

In the 21st century, scientists have acquired more knowledge about cancer and developed modern therapies that involve robotic surgery, immunotherapy, nanotechnology, expression profiling, and proteomics, leading to significant improvement in cancer prevention, early detection, and treatment. However, this does not change the fact that all scientific knowledge is based on the amazing saga of scientific achievements attained by the hard work of our predecessors (Table 1.1). Altogether, it seems that understanding the biology of cancer is just like the blind men and the elephant.

Table 1.1

1.1.2.1 Why does a normal cell become rebellious and kill the body in which it lives?

Multicellular organisms are made up of millions of cells. As per the need of the body, the cells grow and divide. When the cells grow old or become damaged, they die, and new cells replace them. But what happens exactly when the unwanted cells, instead of removal from the body, they stay and wreak havoc inside the body.

To realize how and why cells become rebellious, we need to understand the normal functions of cell growth and reproduction. From the mid-nineteenth century on, biochemists, molecular biologists, and cell biologists have provided astonishingly detailed information about the molecules and processes that allow cells to divide, grow, differentiate, and perform their essential functions. The basic knowledge of cell biology has also led to practical discoveries about the mechanisms of cancer. Specific molecules, that control the progression of a cell through the cell cycle, regulate cell growth. An understanding of the normal cell cycle processes and how those processes go awry provides key information about the mechanisms that trigger cancer. One of the critical steps in the development of cancer is the loss of cell cycle control.

A healthy normal cell does not transform into a cancer cell overnight. The behavior of a normal cell gradually changes by acquiring certain gene mutations (Fig. 1.1) or genetic changes and these changes are sometimes called the Drivers of cancer [2]. Research in cell biology has exposed the Drivers that is, the three main types of genes that contribute to transforming a normal cell – tumor suppressor genes, proto-oncogenes, and DNA repair genes. The alteration of these genes regulation and function are essentially responsible for unregulated cell proliferation and growth leading to neoplasm or tumor formation. As we shall discuss later, the regulation of each driver in the cell cycle.

Figure 1.1 Gene mutation caused by certain environmental factors such as ultraviolet light, ionizing radiations, and chemical carcinogens (e.g., arsenic, cadmium, asbestos) - leads to the production of abnormal proteins that causes uncontrolled cell division and eventually resulting in tumor formation.

Under physiological conditions, cells usually behave in a specific biological manner to sustain a normal healthy life. However, under the pathological condition such as cancer, the nature of the normal cell gets transformed and they behave abruptly. In the following table, we discuss the nature of a normal cell in comparison with a cancer cell (Table 1.2).

Table 1.2

1.2 Neoplasm

The term neoplasm is derived from a mixture of two Greek words, "neo means new, and plasis" means formation. Neoplasm refers to the abnormal tissue growth, caused due to the uncontrolled or rapid division of cells that have undergone some forms of mutations. Unlike normal cells, the growth of neoplastic cells is autonomous that is, independent of growth factors and regulatory mechanisms that commonly operate inside the normal tissues [3]. The uncontrolled growth of the neoplastic cells usually (but not always) forms a mass. When it forms a mass, it may be called a tumor. A tumor mass may be solid, or fluid-filled and are quite different from inflammatory or other swellings. A tumor mass can be felt as a lump, if it occurs on or near the surface of the body, while some are deep sited and may not be palpated [4]. In some instances, tumors may also appear as ulcers, fissures, or wart-like projections. A tumor can occur anywhere inside the body and its size may vary tremendously [5,6].

Like any other tissues or organs, the growth and architecture of a tumor largely depend upon two basic components, such as parenchyma (composed of neoplastic or tumor cells) and reactive stroma (composed of immune cells, fibroblasts, endothelial cells, and specialized mesenchymal cells). The crosstalk between the parenchyma and stroma forms a tumor microenvironment, which is important in deciding the growth and aggressiveness of a tumor [7,8]. For instance, the stromal blood supply promotes the tumor cell division whereas the stromal connective tissue act as a structural framework for growing tumor cells [9]. It is the stromal deposit that decides the nature of a tumor that is, scanty stromal support develops soft tumors while highly collagenous stromal support develops stony hard tumors [10].

Sometimes, the term tumor and cancer are used interchangeably which can be misleading. People often get scared when they get a tissue mass and immediately interpret whether it is a cancer beginning. After intensive research in medical science, it was quite clear that all tumors are not cancerous. Broadly, tumors are classified according to their nature of growth and aggressiveness as benign (non-cancerous) and malignant (cancerous) tumors. The initiation of tumor development is the same for both benign and malignant tumors, such as single-cell mutation, but with time the metastatic potential of malignant tumors always raises a red flag.

1.3 Types of tumor

There are two main types of tumor

1. Benign tumor

2. Malignant tumor or cancer

1.3.1 Benign tumor

A benign tumor is a type of tumor in which the microscopic and gross characteristic appears relatively innocent, implying that it cannot spread to other sites or remain localized. They usually develop a capsular mass that separates it from the normal host tissue. This capsule is just a rim of compressed connective tissue, derived mainly from the extracellular matrix (ECM) of the host tissue. Generally, it can be surgically removed, and the patient may survive. Benign tumors are also called non-cancerous tumors. However, such tumors can sometimes produce more localized lumps, which may lead to serious diseases.

1.3.1.1 Some common types of benign tumors

In general, the suffix –oma is used to designate a benign tumor. Depending on the origin of cells, there are different types of benign tumors. Such as:

Fibroma or fibroids - These are benign tumors of mesenchymal origin. Such tumors are formed in the fibrous tissues of the body. For example, uterine fibroids. Such fibroids are noncancerous but can cause pelvic pain, vaginal bleeding, or bladder problems [11] (Fig. 1.2).

Figure 1.2 Uterine fibroids.

Adenomas - These are benign tumors of epithelial origin, occur in glands or glandular structures. For example, colorectal adenomas (development of tubular or polyp like structure in the colon).

Papilloma - These are warty or finger-like projections that arise from epithelial surfaces.

Note: Most of the benign tumors are non-cancerous; however, some of them if not treated earlier can become malignant.

1.3.2 Malignant tumor

A tumor is said to be malignant when its microscopic and gross characteristics are considered aggressive. Such types of tumors can infiltrate, invade, and destroy neighboring cells and tissues or can spread (metastasize) to distant sites of the body. Malignant tumors are commonly known as Cancer. Generally, malignant tumors are fatal and can cause most cancer death. However, not all cancers are deadly if they are discovered early and are treated successfully.

1.3.2.1 Some common types of malignant tumors

The nomenclature of a malignant tumor is quite the same as a benign tumor, with certain additions. Some of the most common malignant tumors are:

Carcinomas -These are a malignant tumor of epithelial origin. Such tumors are formed in the epithelial cells of the body. For example, hepatocellular carcinoma of the liver, invasive ductal carcinoma (IDC) of the breast (Fig. 1.3), adenocarcinoma of the stomach.

Figure 1.3 Gross pathology photograph of a normal and an Invasive ductal carcinoma (IDC) specimen of a breast mounted on the gel matrix (Modified from Han et al. 2016) .

Sarcoma - These are a malignant tumor of mesenchymal origin. Such tumors are formed in the epithelial connective tissue of the body. For example, osteosarcoma of bones.

1.3.2.2 The characteristic difference between a benign tumor and a malignant tumor

Although the tumor is a distressing designation, pathologists play important role in distinguishing the type of tumor that is, whether benign or malignant, considering various criteria like cellular morphology, mitotic division, cellular differentiation, rate of growth, local invasion, and metastasis. Sometimes, however, pathologists could not make a perfect concordance between the appearance of the tumor and its biological behavior. In such instances, molecular profiling or other molecular diagnoses may provide useful information (Table 1.3).

Table 1.3

1.4 Stages of tumor development leading to cancer

Tumor development is a multistep process. It is initiated when a normal cell in a tissue acquires gene mutations due to different DNA damaging agents, such as chemicals, radiations, and viruses. Usually, cells undergo successful DNA repair mechanism, but sometimes it fails to do so. Further proliferation of genetically altered cells leads to stepwise tumor progression [12,13]. The process described below is applicable for solid tumors, such as carcinoma or sarcoma. Blood cell tumors go through a similar process but since the cells float freely, they are not limited to one location in the body.

Tumor progression occurs in the following steps:

Hyperplasia→dysplasia→carcinoma in situ→invasive carcinoma→metastasis (Fig. 1.4)

Figure 1.4 Different stages of cancer progression.

1.4.1 Hyperplasia

It is a preneoplastic condition and occurs when the altered cell divides in an uncontrolled manner leading to an increase in cell number in that region of the tissue. The cells appear normal in cellular histology, but they are too many. The hyperplastic changes are reversible.

1.4.2 Dysplasia

When additional genetic alterations occur to the hyperplastic cells, an increase in the cellular abnormalities occurs, which leads to dysplasia. The cells of the tissue no longer look normal. The cells in the tissue get an increase in size and number and may become disorganized. This change is somehow reversible, but some types of dysplasia may need to be monitored and treated. In general, the more abnormal the cells and tissue look, the greater the chance of causing cancer.

1.4.3 Carcinoma in situ

More additional genetic alterations make the cells of the tissue appear more abnormal. The cells can now spread over a wider area of tissue. These cells begin to lose their function and are said to be anaplastic or dedifferentiated. These cells display increased n/c ratio and nuclear changes (chromatin clumping), but they are contained within their original location and have not crossed the basement membrane to invade other tissues. Carcinoma in situ is the earliest stage of cancer, and is, at this stage, considered noninvasive and is often curable by surgery. For example, the ductal carcinoma in situ (DCIS) of the breast is confined to the ducts or lobules and does not spread to surrounding tissues or other parts of the body.

1.4.4 Invasive carcinoma or cancer (malignant tumor)

More additional genetic alterations make the cells and tissues appear most abnormal and breach the basement membrane and invade the surrounding tissues and/or spread (metastasize) to other parts of the body. Metastatic tumors are considered the most aggressive and dangerous form. They account for a large percentage of cancer deaths. For example, IDC of the breast has spread beyond the breast, and nearby lymph nodes to other organs of the body such as the lungs, liver, bones, or brain.

1.4.5 Metastasis

It is a process, in which the cancer cells escape and migrate from the primary tumor to other locations of the body to form a new tumor (secondary tumor) through the circulatory system.

1.5 Essential hallmarks of cancer

Over the past two decades, researchers are trying to elucidate the molecular pathology behind cancer and have discovered hundreds of cancers –associated genes. For example, the p53 gene is found mutated in most cancers, the BRCA1 gene is mutated in breast cancer, etc. However, it is essential to understand the cancer-associated genes in the context of malignant transformation. Seven hallmark changes in cellular physiology collectively determine the malignant phenotype [14].

1. Defects in DNA repair - Tumor cells fail to repair the DNA damage caused by carcinogenic agents like viruses, chemicals, and radiations, leading to the genetic instability and mutations of proto-oncogenes and tumor suppressor genes respectively.

2. Self-sufficiency in growth signals - Tumors possess the potentiality to proliferate without external stimuli due to the activation of oncogenes like RAS, RAF, and tyrosine kinase.

3. Insensitivity to growth-inhibitory signals - Tumors may not respond to anti-proliferative molecules like transforming growth factor β and inhibitors of cyclin-dependent kinases.

4. Limitless replicative potential - Tumor cells have an uncontrolled proliferative capacity, avoid cell cycle checkpoints.

5. Evasion of apoptosis - Tumor cells may resist the programmed cell death due to the activation of antiapoptotic genes or mutation of the p53 gene.

6. Sustained angiogenesis - Tumor cells, like normal cells, require blood supply for oxygen, nutrient, and removal of waste products. Hence, tumors must induce angiogenesis.

7. Tissue invasion and metastasis - The tumor microenvironment plays an important role in initiating the tumor cell invasion and metastasis.

Recently, researchers have suggested two additional hallmarks of cancer which they labeled as emerging hallmarks. Such as, the ability to reprogram or modify cellular metabolism to effectively support the tumor cell proliferation and secondly, allows cancer cells to escape immunological destruction by macrophages, B and T lymphocytes, and natural killer cells (Fig. 1.5).

Figure 1.5 Hallmark of cancer.

Among different mentioned hallmarks, some are elaborated in an extensive way for better understanding of cancer such as,

Evasion of apoptosis: An organism has evolved cellular machinery, popularly known as apoptosis or programmed cell death, to eliminate unnecessary or unhealthy cells from the body following cellular stress or in the course of development. Apoptosis is a highly regulated mechanism that involves a series of cellular events, leading to activation of members of cysteine proteases known as caspases. When a cell gets apoptotic stimuli, initiator caspases (caspase -2, 8, 9, 10) get activated, which further cleave and activate the executioner caspases (caspase- 3, 6, 7), leading into proteolytic cleavage of specific cellular substrates and subsequently causing the cell death. Apoptosis occurs by two distinct pathways, intrinsic or mitochondria-mediated pathway (induced due to DNA damage) and extrinsic or receptor-mediated pathway (induced by death receptor binding with death ligands such as Fas and TNF- α). The balance between pro- and anti-apoptotic proteins play an important role in accomplishing the apoptotic mechanism [15].

In a pathological condition like cancer, the cell not only hijacks the normal cellular growth pathways but also escape apoptosis, resulting in the accumulation of tumor cells that might contribute to malignancy. In all types of cancers, it is found that tumor cells, not only retain the inactivation of growth suppressing tumor suppressor genes or activation of growth-promoting oncogenes, but also the mutation in genes that regulates apoptosis, such as BH3-only protein or a caspase. Unlike normal cells, the cancer cell can escape the apoptotic pathway by either altering expression of anti- or pro-apoptotic genes or by stabilizing or de-stabilizing anti- or pro-apoptotic proteins, respectively. For example, p53, a tumor suppressor has been informed to be mutated in most human cancers Fig. 1.6 [16,17].

Figure 1.6 Role of p53 protein in apoptosis and cancer. p53 is a nuclear transcription factor with a pro-apoptotic function. p53 as a classical tumor suppressor play critical role in cancer. In response to stress condition such as DNA damage, wild type p53 get accumulated in the cell nucleus and trans activate target genes like BAX, BID or PUMA to promotes apoptosis and hence prevent the propagation of seriously damaged cell. On the other hand, in most human cancer, p53 is found mutated. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53 and hence display oncogenic potential.

1.6 Metastasis

Most of cancer death is due to the ability of cancer to spread in the body. Doctors often use the term aggressive cancer, advance stage, or stage IV, this means that cancer has spread or metastasized to nearby normal tissues or organs or distant body parts. Metastasis is one of the hallmarks to differentiate malignant tumors from benign tumors. Most of the malignant tumors spread or metastasized to other body parts. In most cases, patients with localized tumors have a better chance of survival than those with metastatic cancer. Metastasis is defined as a multistep process in which cancer cells escape and migrate from the primary tumor to other locations of the body to form a new tumor (secondary tumor). When this happens, it is called metastatic cancer