Molecular Targets and Cancer Therapeutics (Part 1)

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.

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.

The causation of cancer, whether exogenous or endogenous, is a cornerstone of cancer prevention and treatment. Many intrinsic factors are discussed in other chapters of this book; this chapter will shed light on exogenous factors influencing cancer with detailed specific examples of microbial, physical and chemical factors. Microbial role in cancer has been debated over many centuries, whether as an antagonist or a cause, since Imhotep’s time through the mid-17th century when cancer was considered contagious, and later cancer hospitals were forcefully moved out of the cities as isolation camps. There are now vivid evidences that specific microbial pathogens are causing up to 25% of cancer cases (lymphoma, solid or others), and in some cases, a single pathogen was found in association with many types of cancer, such as HPV and EBV, to a lesser extent. Also, several non-biological factors are classified as carcinogens as humans are exposed to millions of chemicals whether in environment or smoke processed food.

Loss of genomic stability in the cell due to defects in the checkpoint of DNA damage, mitotic checkpoint, and telomere maintenance led to increased incidences of base pair alterations. Therefore, that genomic instability plays a critical role in tumor initiation and progression. Tumor progression requires a dynamic tumor/normal exchange in their microenvironment to support tumor growth. The histological alteration seen in the tumor at early stages confirms that the surface between the epithelium and the stroma undergoes progressive disturbance. Tumor progression is also affected by the immune system in which chronic inflammations promote the growth of tumor. Tumor cells experience altered metabolic profiling to support their growth. Cancer cells are characterized by uncontrolled cell division. For that, they utilize glucose as a source of energy to help them grow faster than normal cells. Hence, Glycolysis is a key metabolomics pathway consumed at a high rate during carcinogenesis.

Cancer causes major patient morbidity and mortality and is a critical health concern worldwide. The recent GLOBOCAN 2019 factsheet recorded nearly 19.2 million new cancer cases, 9.9 million cancer deaths and 50.55 million people suffering from different kinds of cancer globally within 5 years after diagnosis. Growth factors (GF) are a group of proteins that can affect cellular processes, including differentiation, division, intravasation, extravasation and dissemination. The circulating tumor cells in the bloodstream can populate distant tissues and organs and believe to be the primary cause of metastasis. Extravasation is a crucial phase in the metastasis process, in which tumor cells leave the bloodstream and enter the host tissue. The progress of metastasis is triggered by the tendency of cancer cells to disseminate to target organs from the site of the primary tumor. Despite extensive basic scientific and clinical investigations, cancer is still a major clinical and public health problem. The development of cancer can be influenced by genetics, environmental factors, gene-environment interaction, lifestyle, age and a number of other factors. The harnessing and enhancement of the body’s own cytotoxic cells to prevent basement membrane rupture and the intervening dissemination processes can provide useful insight into the development of cancer. The mutation in oncogenes and tumour suppressor genes, and chromosomal aberration is a cornerstones of the molecular basis of cancer. The basement Membrane (BM) acts as a cell invasion shield, thus identification of processes that underlie in breaching of BM can contribute to understanding the disease pathogenesis. TGF-β is known for its dual function; it requires inhibition in the advanced stage however, the growth inhibitory properties are displayed in the early stages of tumorigenesis. Therefore, inhibition of TGF-β signalling in the CD8+ T cell compartment may be necessary for tumor immunity to be restored. Quantitation of tumour cell dissemination is important and plays significant role in elucidating mechanisms of cancer and strategies for therapeutic intervention. 

Cancer is characterized by atypical cell proliferation that has the possibility of dissemination to different body parts. Tumor formation is influenced by genetic mutations and environmental pollutants. The formation and progression of malignancies have been linked to a diversity of molecular paths. The JAK/STAT, NOTCH, PI3K/AKT pathway, mitogen-activated protein kinase (MAPK), transforming growth factor-beta (TGF-beta) (TGF-), NF-B, and Wnt signaling pathways will be highlighted in this chapter. Cancer development has been linked to various changes to the signaling pathways' components. As a result, various initiatives to target signaling pathways in order to build distinct treatment lines have been approved. In this chapter, we discuss the role of signal transduction in cancer-associated processes and how their targets influence the behavior of the tumor cells.

Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.

Despite variations in the morphology and behaviors of human body cells, every single cell in our body is composed of identical DNA material. The variation in cell phenotypes is a result of a specific regulatory mechanism known as epigenetics, by which gene expression undergoes some modifications without the actual nucleotide sequence being affected [1]. This phenomenon is accomplished through several mechanisms, such as cytosine residue methylation, modifications of histone units, and RNA interference. Therefore, epigenetics performs a key function in embryonic growth and development, cellular RNA expression, gene imprinting, and silencing of females’ X chromosomes [2]. Any impairment in these mechanisms may cause various human disorders, including cancer [3]. In carcinogenesis, defective epigenetic machinery at several distinct levels results in abnormal cellular functions [4]. This chapter highlights epigenetics' importance in cancer development and its potential applications for cancer treatment.