The earliest proof of the existence of human cancer is the bone tumors discovered in a fossilized hominid, which dates back 4 million–years. Egyptian mummies from 3000 BCE also bore nasopharyngeal carcinomas and osteogenic sarcomas (Javier & Butel, 2008). Babylonian Code of Hammurabi (1750 BCE), ancient Egyptian papyri (1600 BCE), the Chinese Rites of the Zhou Dynasty (1100–400 BCE), and the ancient Indian Ramayana manuscript (500 BCE) are ancient written records of human civilization, and interestingly they have references for cancer. Later the Greek philosopher theorized that the human body is made of blood, phlegm, yellow bile, and black bile in proper proportion, and aberration of their proportion leads to different diseases and cancer originating from excessive black bile. The Romans later developed the Greek theory as well (Diamandopoulos, 1996).

At the dawn of the 19th century, a new branch of science focusing on cancer research emerged and was termed oncology. Due to the invention of the microscope, scientists confirmed it to be a cellular disease. In 1926, the Nobel Prize was awarded for identifying nematode worm-inducing stomach cancer in rats. Finally, in the 20th-century cancer research found its footing with the discovery of avian tumor viruses when Dimitrii Ivanofsky and Martinus Beijerinck became the fathers of the new field of virology as they reported that infectious pathogens of tobacco plants maintain virulence. Shortly later, viruses were discovered, and more animal and plant viruses were identified (Wormser & Rubin, 2002). Near the end of the century, papillomaviruses were associated with human cancer. However, as more and more studies could decipher various causes, the most common was mutations of various genes.

Malignant tumors are broadly classified into two forms. Based on their form: (a) solid tumor cancer, (b) blood cancers, or hematological cancers. Solid tumors are further classified as sarcomas, carcinomas, and lymphomas based on their cells of origin. Briefly: (i) If the tumor originates from the epithelial layer of organs like the skin, gastrointestinal tract, internal organs, or anatomical sites, it can be considered carcinoma. (ii) if they originate from muscle, adipose, bone, or blood vessels, they can be considered sarcomas; (iii) if they originate from lymphoid tissue, they can be considered lymphomas; (iv) rare histo-types (Carbone, 2020) (Fig. 1). Another way of classifying tumors is the grading system accepted by the World Health Organization, which takes together the cytological morphological and structural features, and this grading system is often specific for certain types of tumor (Rosai & Ackerman, 1979). As solid tumors comprise a heterogeneous group originating from various organ systems and are not entirely curable by chemotherapy, more studies on pathways involved in the initiation and progression of their tumorigenesis are necessary at the current time (Cronin et al., 2018).

Some of the most common carcinomas are breast, lung, colon, prostate, non-melanoma of skin, stomach, liver, rectum, pancreas, kidney, and ovary (Sung et al., 2021). Despite having a varying origin, all solid cancers show aberration of at least one signal transduction pathway, and this change from normal physiologic function often causes tumor initiation and progression. Hence, identifying the signaling molecules initiating the cancer and targeting it for therapeutic strategies has been a consistent research interest among cancer researchers (Juliano, 2020). Identifying new molecular and genetic alterations provides insight into the biology of sporadic cancers and helps identify novel treatments or personalized medicine for cancer. However, although sometimes targeting specific molecules shows promising preclinical results, factors like developing resistance or dose toxicity often led to failed clinical trials. Hence, constant evaluation of cell signaling pathways in cancer is required to identify novel targets for more remedial options. Some of the oncogenes like MYC, RAS, BRAF, KIT, and tumor suppresser genes like TP53, BRCA1, and PTEN were not only discovered during the early period of cancer research, but they are also associated with most solid tumors (Consortium, 2020, International Human Genome Sequencing, 2004, Yip and Papa, 2021).

Reports state that 90% of adult human cancers are solid tumors. In contrast, only 40% are solid in children, and some of the most prevalent solid tumors are of lung, liver and bile duct, stomach, kidney, endometrial, colon and rectal, breast, bladder, thyroid, prostate, pancreatic, and melanoma. Solid tumors lead to mortality, and severe morbidity among cancer survivors is also prevalent. Solid tumors involve the transformed malignant cells and induce changes in the surrounding microenvironment, which involves other cells, such as immune cells. Sometimes, the abnormal tumor microenvironment (TME) drives the tumor progression, invasion, and metastasis, leading to drug resistance inducing drug delivery and sensitivity challenges. Thus, pathways that cause these challenges in solid tumors must be studied to identify various targets and improve therapeutic efficacy.

At present, cancer is commonly treated by surgery, radiation therapy, chemotherapy, combination therapy, and laser therapy. The treatment options are selected based on the knowledge about the biological and molecular mechanisms that had led to tumor progression in the first place. Unfortunately, despite these advances and the promise that chemotherapy holds, it often fails due to acquired drug resistance, which results in recurrence. Some causes of acquired drug resistance include tumor heterogeneity, TME, activation of cancer stem cells (CSCs), inactivation of the activity of drugs or increasing release of drugs outside the cells, reduction in drug absorption, change in drug metabolism, and secondary mutation in drug targets. Hence, to mitigate this significant problem in cancer treatment, novel, and extensive studies are constantly going on to identify more molecular targets of oncogenes and tumor suppressor genes, improving the rapid immune responses in cancer, Specializing the medications such as personalized medicine, novel and innovative way of drug delivery into the tumor and ameliorating drug side effects (Mansoori, Mohammadi, Davudian, Shirjang, & Baradaran, 2017).

The most important hallmark of cancer cells is uncontrolled and rapid cell division, mainly due to genetic and epigenetic alterations in cancer genes or genes of associated signaling pathways resulting in either over-proliferation or evading normal cell death mechanisms. Thus, physiologic changes in cell signaling pathways are extensively studied in cancer to understand the initiation and progression of tumorigenesis and develop new treatments for precision medicine in cancer, such as small molecule inhibitors and monoclonal antibodies targeting cancer-related proteins (Yip & Papa, 2021). Identifying responsible oncogenes and tumor suppressor genes leads to more advanced pharmacologic-targeted cancer therapy. In the case of solid tumors, the reported alterations mainly transform a comparatively benign group of proliferating cells (hyperplasia) to a solid mass of cells with morphological, cytological, and organizational abnormalities. As the tumor grows, the core becomes hypoxic, and to meet the demand, new blood vessels start developing by angiogenesis. As the tumor progresses, it can invade the tissue beyond its physiologic boundaries, enter the circulation, and develop new tumors at other locations, causing metastasis. Thus, all the cell signaling pathways whose aberrant physiologic functions lead to the development of malignancy must be studied in detail to develop novel therapeutic strategies, especially for rare cancers (Sever & Brugge, 2015).

Cell signaling pathways play a pivotal role in cancer. They are mainly involved in processes like cell proliferation, apoptosis, metastasis, and maintaining the stemness of CSCs. Some of the most widely studied pathways are Mitogen-activated protein kinase (MAPK), Sonic hedgehog (SHH), phosphoinositide-3-kinase/AKT/The mammalian target of rapamycin (PI3K/AKT/mTOR), NOTCH, Wingless and Int-1/β catenin (WNT/b catenin), Hippo signaling, p 53 signaling, Programmed Cell Death Protein 1-Programmed Cell Death Ligand 1 (PD-PDL1), Heat shock proteins (HSPs) and endocrine pathways. In this chapter, we discuss some of the most widely studied cell signaling pathways, which are altered compared to their normal physiology in solid tumors, the most significant alterations, and how they are potentially targeted for therapeutic purposes.

Historically, the initial strategies for treating cancer (chemotherapy and radiation therapy) focused on targeting any actively growing cells rather than targeting only cancer cells. However, the side effects were detrimental to the patient’s health and required alternate propositions. An extensive and in-depth understanding of the overactive signaling pathways in cancer cells, which vary functionally from normal cells, can help to develop treatments targeting more effectively cancer cells only, sparing normal cells. As solid tumors have dysregulation in one or more of the different cell signaling pathways, it is crucial to identify the functional protein responsible for the tumorigenesis of a particular cancer and develop the drugs to target it. So, this targeted therapy is one of the most promising strategies for improving treatment outcomes in various cancer patients. However, cancer is also an evolving disease, and most patients eventually develop resistance to these drugs by acquired mutations or mediation of microenvironmental factors or simply due to tumor heterogeneity. Researchers are trying to develop a combination therapy approach targeting multiple responsible pathways effectively. Thus, in-depth knowledge of cell signaling, and its components remains a critical topic of cancer research.