Colorectal Cancer: Disease and Advanced Drug Delivery Strategies

By Sankha Bhattacharya

Colorectal Cancer: Disease and Advanced Drug Delivery Strategies examines the combined impact of basic clinical and medical treatments as well as recent advances in the field of colorectal cancer.

With a strong focus towards colorectal cancer diagnosis, disease drug delivery, and diagnosis, the book also examines the Tumor microenvironment-responsive and site-specific nanoparticles for cancer theragnostics.

In 16 chapters Colorectal Cancer: Disease and Advanced Drug Delivery Strategies not only provides the opportunity to understand and diagnose the disease, but it also describes screening methods, drugs including nano- and immunotherapy, and gives insight into the role of nanoparticles, lipids, and biomarkers in colorectal cancer. Content includes clinical trials in colorectal cancer research and disease models. This book directs researchers and clinicians how to better diagnose and treat colorectal cancer.

• Provides a wealth of information on the latest research and developments in the science and treatment of colorectal cancer
• Contains new and innovative ways to treat colorectal cancer
• Reflects on basic clinical and medical methods and recent advances in colorectal cancer science
• Gives specific details about how nanoparticles can be used to target cancer cells or cancer treatment
• Covers tumor microenvironment, their challenges, and opportunities in colorectal cancer research

• Language: English
• Publisher: Academic Press
• Release date: Nov 19, 2023
• ISBN: 9780443138713

Book preview

Chapter 1

Colorectal cancer: understanding of disease

Lucy Mohapatra¹, Alok Shiomurti Tripathi², Deepak Mishra¹, Mohammad Yasir¹, Rahul Kumar Maurya¹, Bhupendra G. Prajapati³ and Alka¹,    ¹Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India,    ²Department of Pharmacology, ERA College of Pharmacy, ERA University, Lucknow, Uttar Pradesh, India,    ³Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-Mahesana, Gujarat, India

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed carcinoma condition. The biological mechanisms of inherited and infrequent CRC are being explored. A few lines of indication prove that lifestyle influences, to some extent, may be accountable for the widely held variability in CRC and contribute to the risk within populations. The different molecular pathways, including the endothelial growth factor receptor (EGFR) pathway, vascular endothelial growth factor receptor pathway, and Wnt pathway, are the important pathways involved in the pathogenesis of CRG and have been discussed broadly in this chapter. Wnt/β-catenin helps in the progression of stem cell-specialized repairing and protection and colonic crypt oocyte proliferation. The major molecular systems and driver genetic mutations implicated in engaging and spreading the cascade of signal transduction that reaches cancer and forceful metastases of CRC are covered in this chapter. Despite the recent advances in therapies, a greater awareness of the molecular strategies and hereditary interference in CRC is supposed to play a significant part in promoting the emergence of novel and targeted treatments with better safety features. Targeted therapy is an innovative additional strategy that has successfully improved CRC patients’ survival rate. Recent developments describing the success of the anti-EGFR agent like CTAb and the antiangiogenesis agent bevacizumab in CRC, blocking numerous significant pathways in the pathogenesis, are being established as major treatment strategies at a rapid rate. Hence, special focus has been given to significant developments in CRC treatments exploring macromolecular targets like KRAS, BRAF, APC, PIK3CA, and PTEN.

Keywords

Colorectal cancer; etiology; wingless related integration site; epidermal growth factor receptor; ras; mutation

1.1 Introduction

Colorectal cancer (CRC) is the growth of tumor from the portion of the large intestine, which is the colon or rectum, that leads to stool containing blood or problems regarding the motion of the bowel and even situations like weight reduction along with fatigue [1]. CRC is also termed as colon or rectal cancer depending upon the site where it is initiated. CRC cases may rise by 60% by 2030, making it the third most prevalent cancer detected globally and the 4th most frequent contributor to fatality related to carcinoma conditions [1]. Genetic, ecological, and lifestyle risk aspects all contribute to the cause of CRC. The illness called CRC, which only attacks the colon or rectum, is driven by the colon’s uncontrolled cell growth of secretory epithelial cells. The three primary subtypes of CRC are sporadic, inherited, and colitis related. Globally, CRC cases are expanding nearly daily [2]. Along with improving socioeconomic circumstances, economic growth and civilizational advancement influence eating habits or the westernization of lifestyle. A significant going to consume carbohydrates, highly processed meats, fats from animals or desserts, a diet lacking fibers, fruits, vegetables, and minimal exercise are all implications. Such a way of living usually causes overweight or obesity [3]. Obesity and being overweight are connected to an increased risk of many contemporary diseases. Viscerally obese men have been proven to have a worse prognosis when they have CRC [4]. The stages that make up the formation of CRC include initiation, promotion, and advancement. Due to irreparable genetic damage at the commencement, the damaged intestinal mucosal epithelial cells are susceptible to a subsequent neoplastic transformation [5]. During the promotion phase, abnormal growth happens when the starting cells multiply, that is, cancer is formed.

On the other hand, mild cancer cells transform into cancerous tumors at an elevated level, acquiring aggressive traits that lead to developing the capacity to spread throughout the body [6]. Most CRC carcinogenesis phases require a polyp-type benign precursor lesion, which is essential. The large intestine lumen has also been observed to develop serrated polyps and adenomatous polyps, which are the early stages of most malignancies [7]. Advanced adenomas (1 cm in diameter) have a considerably greater probability of developing cancer (between 30% and 50%) compared to partially developed adenomas (1%), with or without variety. Higher rates of cancer progression are seen in elderly patients with advanced adenomas [8]. There were over two million first-time incidents in 2020. With an approximate fatality of 10 lakhs each year, CRC is the second most prevalent cause of all carcinoma-related deaths. One of the cancers with an increasing incidence, it represents 11% of all cancer cases globally [9]. According to GLOBOCAN 2020 statistics, there are considerable various changes in the incidence and mortality of CRC [10]. A study revealed that between 2007 and 2016, the prevalence of colon cancer increased in 10 of the 36 countries it examined (all in Asia or Europe); this rise was most apparent in Poland and India, depending on when the information was available [10]. The 10 countries range from average to high on the HDI. Under-50s were more likely to develop colon cancer in eight countries, including the UK and India. Germany, Australia, the US, Sweden, Canada, and the UK were among the countries with a declining or steady incidence among those of age 50 and older, but a sharp rise in those under 50 has been observed [11]. Age-standardized (global) mortality for CRC is almost 9 per 100,000. Several variables are suspected to contribute to the onset of CRC [12]. It has been shown that those who have had cancer, tumor fragments, diabetes mellitus, irritable bowel syndrome, or cholecystectomy, either themselves or through a close relative more likely to get CRC. Lifestyle factors are an essential part of the growth of CRC [3,4]. The risk of CRC may be increased by physical inactivity, smoking, drinking, being overweight or obese, and eating incorrectly (a diet strong in red and preserved cold meat and lacking in fruits, vegetables, fibers, calcium, and other nutritious goods). The chance of CRC is also known to be influenced by the gut microbiota, aging, sex, ethnicity, and socioeconomic status [4,13].

Growing interest has been shown in identifying biomarkers that can be used to diagnose, monitor therapy outcomes, and predict outcomes of CRC [14]. Recent advances in such technology related to molecular and proteomics have helped researchers to distinguish changes in protein, and small molecules from small amounts of tissue [15]. Blood-based markers can enhance the efficiency of treating cancer when they are accurately characterized and can be evaluated quickly and easily [16]. In this chapter, we presented the major driver mutations responsible for the progression of CRC along with the associated molecular pathways. The growth factor pathways VEGFR, EGFR, Wnt, PI3/AKT, HGF/cMET, and APC, TP53, and TGF have been broadly discussed in this chapter with the main tumor suppressor genes that can be inactivated, as well as the genetic mechanism behind microsatellite instability in the progression of CRC. For each pathway, a summary of numerous key virtual screening experiments has been provided that involve finding hits and/or optimizing lead compounds for each unique protein target.

1.2 Understanding of disease: colorectal cancer

1.2.1 Etiology and pathogenesis

Lifestyle influences are the major causal factors playing a pivotal role in the progress of CRC [3,4]. The menace of CRC might be amplified by physical inactivity, smoking, drinking alcohol, being overweight or obese, and eating incorrectly (a diet strong in red and preserved cold meat and lacking in fruits, vegetables, fibers, calcium, other nutritious goods). The risk of CRC can also be influenced by gut microbiota, aging, sex, ethnicity, and socioeconomic status [4,13]. Fig. 1.1 depicts the important etiological factors involved in the pathogenesis of CRC.

Figure 1.1 Etiological factors giving rise to the initiation of Wnt signaling pathway leading to colorectal cancer (the factors such as alcohol consumption, dietary fat and meat consumption, smoking, etc.) activate different cascade, mainly Wnt cascade. The various etiological Wnt/Beta-catenin cascade is defined as the connection of Wnt and the underlying receptor complex, comprising ten proteins from the FZD family and either LRP5 or LRP6. The activation leads to cancer cell proliferation, autophagy, apoptosis, and other major factors that contribute to the progression of colorectal cancer. Wnt, Wingless related integration site; Axin, is a recently identified tumor suppressor; GSK3, Glycogen synthase kinase 3; TCF, transforming growth factor.

1.2.1.1 Environmental factors correlated to the incidence of colorectal cancer

According to several lines of research, many variations in CRC risk among populations may be caused by environmental variables. Given that the human genetic code usually undergoes changes over a long period of time. The fact that colon cancer incidence has been consistently increasing in affluent nations since the onset of the 21st century indicates that ecological or lifestyle variables may be important [17].

1.2.1.1.1 Dietary fat and meat intake

People who consume large quantities of red meat and animal fat are thought to increase the likelihood of colon cancer [18]. In most of the case-control and many futuristic studies [19], a collaboration among red meat with a large amount of fat consumption and elevated incidence of CRC has been observed. A high-fat diet promotes bile acid secretion, and colonic bacteria can convert bile acids into carcinogens, which is one reason for the link between fat and CRC [20]. Another theory centers on the creation of carcinogenic heterocyclic amines during the preparation of animal protein in high temperatures, like red meat [21]. The notion that cyclic amines could be essential in the pathogenesis of CRC is substantiated by connections between both the integrity of NAT-1/2 acetylation red and processed meats, in addition to linkages among excessive consumption of red meat and the frequency of CRC [22–24].

1.2.1.1.2 Vegetables, fruits, and fibers

The vegetable fiber found in foods is supposed to reduce the incidence of CRC, likely by accelerating bowel movement and the quantity being reduced the carcinogenic substances in feces. Most epidemiological studies show an inverse connection between vegetable fiber and disease risk [25,26]; however, the evidence for the preventive effects of grains is arguably weaker [27–29]. However, another component of vegetables and fruits, such as folate or antioxidative supplements of vitamins, is probably the cause of this beneficial response.

1.2.1.1.3 Smoking Cigarette

Smoking increases the risk of acquiring colon tumor, but it has not been linked to an elevated incidence of CRC in general [30]. Most studies have failed to find a link between smoking and the incidence of CRC [31–33]. The early age at which people begin smoking has been linked to colon cancer, which may indicate a very extended period between the tumor’s commencement and the clinical diagnosis [34].

1.2.1.1.4 Alcohol

The high consumption of alcohol and the incidence of CRC has been attached in ecological studies. To date, all population-based cohort studies and a handful of other studies suggest a strong relation between heavy episodic drinking and the probability of CRC [35–37]. However, Longnecker et al. found that the data is insufficient to conclude that the correlation between alcoholism and the occurrence of CRC is causative because of the poor overall association between alcohol and that risk, as depicted in Fig. 1.1, where alcohol is seen to cause the activation of major etiological pathways including the Wnt- pathway contributing to the progression of CRC [38].

1.2.1.2 Genes involved in the prognosis and pathogenesis of colorectal cancer

The CRC condition develops from the colon segment, the epithelium, and the other parts, such as the rectal portion of the gastrointestinal system. Vogelstein et al. [39] established the first structured form of the interplay of target genes and tumorigenesis in the evolution of CRC. CRC is caused by mutations inside 3–6 genes that show the gene-targeted model. As a response, it has been discovered how abnormalities in the protooncogene like K-RAS and N RAS, in addition to the tumor suppressor markers APC, DCC, p53, and MCC, directly participate in the malignant transformation sequencing of CRC [40]. The Wnt Signal transduction pathway is the most recurrent alteration in such malignancies. These abnormalities are inherited and can occur in the gastrointestinal crypt stem cells. The APC chromosome, which encodes the APC polypeptide, is the gene that is disrupted most frequently across all kinds of colon cancer. Without an APC molecule, β-catenin accumulates to high proportions and reaches the interior, where it interacts with DNA and stimulates the gene transcription that is ordinarily critical for cell therapy regeneration, segmentation, and tumor growth.

On the other hand, this can lead to malignancy if highly expressed. The tumor suppressor TP53 generates the p53 molecule, which periodically controls the replication process and kills cells with abnormalities in the Wnt pathway. Ultimately, a human cell acquires a TP53 mutated gene, which induces the material to transform from an adenocarcinoma to an invasive neoplasm. Apoptosis-inducing enzymes are suppressed in CRC and TGF-beta and abolished in CRC. In CRC, other gene mutations that can create polypeptide, like Phosphatidylinositol, RAF, and KRAS, are predominantly expressed, encouraging unchecked tumorigenesis [41]. Colon cancer appears to have a wide range of causes. Familial illnesses such as Genetic Nonpolyposis CRC and FAP are seen in conjunction with HNPCC. Accidental colon carcinomas are colon cancers that seem to be unattached to a condition of familial predilection [42,43].

1.2.2 Pathways involved in pathogenesis of colorectal cancer

BRAF, KRAS, NRAS, and PIK3CA are the few types of oncogenes that promote tumor progression, and some of the major tumor suppressor genes are TP53, APC, SMAD4, and PTEN are examples of etiological factors that can contribute to CRC occurrence. These etiological factors also deregulate key signaling pathways driving progression in CRC carcinogenesis. These signal transduction pathways comprise PI3K, MAPK, TGF, WNT/β-catenin, and epidermal growth factor receptor (EGFR) [44]. The prognosis of CRC is thought to be influenced by a number of mechanisms, some of which have been described in this chapter. These pathways include the EGFR route, the VEGF/VEFGR, Wnt system, PI3/AKT, and the HGF/cMET mechanism [44].

1.2.2.1 Epidermal growth factor receptor pathway

Several ErbB/HER (erythroblastosis oncogenic B/EGFR protein) family members would comprise the EGFR circuit. Among the many receptor tyrosine kinases, receptors like ErbB were initially thought to have a relationship to cancer about three decades ago. Due to HER3/decreased ErbB3 kinase activity along with the lack of a ligand for ErbB-2 linked to HER-2, such membrane protein is only induced following heterodimers or heterodimerization of HER-2, HER-3, or HER-4 by binding directly, primarily by EGF or TGF-alpha [45,46]. The JAK/STAT3 pathways, as well as the PI3K/AKT and MEK/ERK along with the Ras-Raf pathway, are some downstream intracellular signaling pathways that are stimulated to modulate the growth of cell and their survival and migration after being activated [47–49].

In addition to suggesting a bad prognosis, 20%–30% of carcinoma demonstrate upregulation of EGFR, 60% of NSCLCs, and approximately 75% of CRCs [50–52]. Approximately 20%–30% of breast and ovarian malignancies [26], about 37% of GIT cancers [53], and 1.3%–47.7% of CRCs overexpress HER-2. However, realizing it was extremely tricky to find its target, this was barred from being a pharmacological target. Compared to noncarcinoma tissues, HER3 exhibited increased action in about 84% of gastrointestinal tumors and 20% of ovarian, breast, and bladder carcinoma. The many downstream effectors that EGFR activates play a pivotal display in the progression followed by cancer growth by controlling cellular proliferation or metabolism. Activated EGFR first wants to recruit SOSs to the plasma to trigger RAS-RAF. This process phosphorylates MAPK or MEK and excites the important ERK, which causes its translocation inside the nucleus to control c-FOS and ELK-1 upregulation, some of the transcriptional regulators [54–56]. It is important to note that the Raf family, BRAF (BRAF protooncogene), plays crucial functions in the Ras-Raf-MEK cascade during RAS-RAF stimulation as shown in Fig. 1.2. Phosphorylation of the second messenger phosphatidyl-inositol-bisphosphate (PIP2) occurs from the stimulation RAS or EGF to access the system along with PI3/K. The PKB also regarded as AKT, which has been recruited to the cell membrane, interacts with PIP3 through its SH3 domain. AKT is a crucial regulator in the ErbB-related pathway and plays important roles in cell proliferation, leading to apoptosis [57–59]. In contrast, of every ErbB-dimer family member, the ErbB2–3 heterodimer is the most potent PI3K/AKT pathway activator. Poorly controlled hyperglycemia and malignancies have both been linked with upregulation [32]. Through the stimulation of a BCL-2-associated modulator of cell death and GSK-3, AKT controls cell cycle transition and survivability. It also suppresses apoptotic death by engaging the mammalian target of rapamycin [60].

Figure 1.2 Vascular endothelial growth factor (VEGF) and endothelial growth factor (EGF) pathways involved in the pathogenesis of Colorectal Cancer. EGF stimulates the Jak/STAT pathway along with paths comprising Mitogen-activated and PI3K/mTOR/Akt when interacting with the EGFR. Its activation leads to angiogenesis, and proliferation and inhibits the apoptotic bodies that lead to the development of CRC. PTEN also helps in inhibiting the PI3K pathway. Cetuximab and panitumumab are EGFR-targeting antibodies. The PI3K/Akt/mTOR pathway is activated when VEGF interacts to the VEGFR. EGF, Epidermal growth factor; mTOR, mammalian target of rapamycin; Akt, Ak strain transforming; Jak, Janus Kinase; STAT, signal transducer and activator of transcription; CRC, colorectal cancer; PTEN, phosphatase and TENsin homolog deleted on chromosome 10; EGFR, epidermal growth factor receptor.

1.2.2.2 Vascular endothelial growth factor receptor pathway

Tumor start, development, and metastasis are all greatly influenced by angiogenesis, a biological function whereby new blood vessels develop or reconstruct from pre-existing vessels. Additional fissional and antiproliferative agents, including VEGF, fibroblast growth regulators, and PDGF produced by tumor or oncogenes, are implicated in the delicate modulation of angiogenesis [61–63]. Before the discovery of VEGF-A, also called vascular endothelial growth factor (VEGF), and the development of a prohibitor target of such monoclonal Ab, which definitively showed the progressive effect on tumors related to angiogenesis, the association between neo-vessels and carcinogenesis was only hypothesized [63]. The cases of CRC and other tumors have raised in numbers of VEGF and elevated numbers of vascular endothelial growth factor receptor (VEGFR) activity, as depicted in Fig. 1.2, which are considered markers of a bad prognosis [64–67]. It’s indeed conceivable that VEGF acts as both an endocrine and an autocrine factor in this situation because some tumor cells both make and exhibit VEGFR. Early colorectal neoplasia, like adenoma, was associated with elevated VEGF levels, and later cancer stages, particularly the metastatic stage, showed much greater levels of VEGF [68,69]. In CRC, VEGF is complexly regulated. As depicted in Fig. 1.2, mutations in K-RAS and p53, Vascular endothelial growth factor interaction may well be influenced by Cyclo-oxygenase 2 transcription, HIF-1, and high malignant cells concentration, which then, in turn, affects tumor growth and mobility [70–72].

1.2.2.3 Wnt pathway

Three channels in the Wnt/β-catenin pathway, also known as that of the canonical Wnt transmission system, the Transcription factor route, and the Wnt-Ca2+ transmission pathway, are some of the different branches of the signal cascade. Wnt pathway is the center of concern of the current study. Downregulation of this network on the Wnt/ β-catenin branch is linked to various disorders [73].

1.2.2.3.1 Canonical Wnt/β-catenin pathway

This type of Wnt coupling with its own principal signaling cascade receptor, consisting of ten proteins from the FZD family and either LRP5 or LRP6, defines the Wnt/β-catenin pathway [74]. GSK3, CK I, Axin, and adenomatous polyposis are the components of a complex that phosphorylates cytoplasmic β-catenin in the stable and related ligand. Axin is the form of a compound that aids in developing a bond with GSK3 and APC. As quickly as the reaction occurred, GSK3 boosts β-catenin’s nuclear kinase activity, and APC facilitates the cell’s adherence to the intracellular proteolytic route. If a large number of Wnt peptide receptors, the signal attaches to the cell’s basic response element and stimulates Wnt transmission by employing the subcellular protein to attempt to halt or destroy the assembly of the Axin/GSK3/APC group. This prohibits β-catenin from deteriorating and lets it aggregate in the cytosol. The intracellular β-catenin slowly builds and diffuses into the nucleoplasm, which links up with the transcriptional activation to initiate the interpretation of Wnt gene mutations. Wnt/β-catenin transmission promotes the maintenance and preservation of the niche of stem cells and the proliferation of colonic crypt oocytes. The bulk of colorectal carcinoma have mutations that trigger the Wnt/β-catenin system to be triggered. Nuclear β-catenin is upregulated due to Wnt transcriptional regulation via downregulating GSK3 activity [75].

1.2.2.3.2 Noncanonical pathway

A noncanonical signaling pathway is defined as one that is independent of -catenin TCF/LEF and that controls both transcriptional and nontranscriptional responses in cells. Two of the most frequent β-catenin dependent Wnt pathways are the Wnt/Ca2+ pathway and PCP [76].

Cancer cell proliferation

Numerous biochemical processes, such as proliferative, stem cell activation, apoptotic signaling, autophagic cell death, metabolism, immunology along with the immunization, diversity, resistance, ion channel, EMT, and migration along with invasion are all characteristics of cancer cells which are all influenced by the Wnt signaling pathway. Three crucial elements of the cascade—the Wnt ligand and receptor interface, TCF/ β-catenin transcription complex and the β-catenin disruption complex have been identified as candidates for preclinical and clinical assessment treatments [77]. The transcription factors tissue connection recognized as the Wnt/β-catenin up-regulation is crucial for cell therapy renewal, gene expression, and chromosome segregation throughout gestation and adult cellular homeostasis [78].

Stemness

These cells’ ability to differentiate and renew again is the description of these cells [78]. In several such adult cells, the usual Wnt/ β-catenin signaling pathway is essential for controlling the excellent harmony among specialization and drying as in the case of mammary ducts, gastrointestinal, and hairs follicle in the epidermis. Therefore, the fundamental source of cancer in such regions is persistent. Variations in the genes that produce its descending elements enable the Wnt signaling to respond [79]. Wnt signaling controls adult tissue homeostasis and embryonic development. The Wnt pathway is extensively exaggerated by two tributaries, controlled by β-catenin called the classical pathway. At the same time, the other is designated as the unique pathway for the downstream target throughout development by phospholipase C (PLC) and small GTPase. Recent research has shown that wingless/integrated (WNT) plays an important role in preserving stem cellular components metabolism, including via neoplastic remodeling, that improves cancerous cells viability, diversification, multiplication, and divergence in addition to a stress reaction and tolerance, tumor growth, and tumorigenesis are downregulated [80].

1.2.2.4 PI3/AKT pathway

A heterodimer enzyme called PI3K adds a phosphodiester to the inner membrane’s inositol to create PIP3. PKB, known as AKT, is a downstream PI3K and EGFR effector. AKT is activated due to an interaction between AKT and PIP3, and other effectors are subsequently phosphorylated, which affects a number of cellular processes, including growth, survival, apoptosis, migration, and cancer progression [81,82]. It is vital to memorize that the two main signaling pathways used by the EGFR are the RAS/RAF/MAPK/ERK and the PI3K/AKT/PTEN/mTOR [61]. In 60%–70% of CRC, the PI3K/Akt pathway is active, and this activity is correlated with better detection in the case of stage two colon cancer [83]. Therapeutic targets for CRC include inhibitors of this pathway, but point mutations and genomic alterations in resistance studies may provide a more true depiction of the prognostic feature of CRC [84].

1.2.2.5 Hepatocyte growth factor/cellular mesenchymal-epithelial transition factor pathway

Hepatocyte growth factor (HGF), which belongs to the cytokine family, specifically binds to the kinase receptor c-MET. Increased cancerous cells’ metabolic route and growth, increased EMT, penetration, dissemination, and treatment response are just a few of the effects of this pathway being upregulated, which is linked to a number of cancers, including CRC [85,86]. In this respect, a boost in the HGF/c-Met dependent cascade and CD4+ forkhead box (Foxp3)+ along with Tregs, which are nothing, but the regulatory form of the T cells, has been visualized. These factors inhibit cytotoxic T cells, leading to increased metastasis and invasion [87]. Basic carcinoma, hepatic, colonic mucosa, and metastatic carcinoma hepatocytes were all examined for c-MET expression. The highest levels of c-MET expression in CRC liver metastases were found to be connected with advanced disease stages, invasion, and poor detectability [88]. Additionally, utilizing miRNAs such as MIR-1/34,141,199/206 to inhibit this pathway seemed promising [89]. This pathway promotes the diffusion and binding of tumor cells in an animal model with pre-existing metastasis [90]. Due to the presence of many lipid precursors cells and (IV) activating numerous signaling cascades that result in MDR [91]. In MDR cancer cells, the ABC membrane transporter p-gp is overexpressed. It has been discovered that MDR can be defeated by downregulating p-gp by targeting the PI3K subunits P110a and P110B. The genome-wide studies firmly establish a connection between human CRC and frequently altered driver genes, as illustrated in Fig. 1.3 [92].

Figure 1.3 Various driver genes and the signaling pathways they target leading to colorectal cancer (CRC). In the transition of healthy epithelium to the metastatic stage in CRC, the driver genes and signaling pathways are implicated across the CRC adenoma–carcinoma sequence. APC mutations typically co-occur with TP53 or KRAS mutations, or both. This triad indicates a bad prognosis, unlike BRAF, CBX4, CSMD3, FBXW7, ITGB4, SYNE1, and TAF1L, which strongly associate with MSI but not metastatic disease. IRS2, Insulin receptor substrate 2; MDM2, mouse double minute 2 homolog; mTOR, mammalian target of rapamycin; PAK4: p21 (RAC1) activated kinase; AKT, Ak strain transforming; APC, adenomatous polyposis coli gene; Bax, Bcl-2-associated X protein; BRAF, rapidly accelerated fibrosarcoma homolog B1; CBX4, Chromobox 4; CSMD3, CUB and Sushi multiple domains 3; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transitions; ERK, extracellular signal-related kinase; FBXW7, F-box with 7 tandem WD40; IRS2, insulin receptor substrate 2; ITGB4, integrin β-4; KRAS, Kirsten rat sarcoma virus; MAPK, mitogen-activated protein kinase; MDM2, mouse double minute 2 homolog; MEK, mitogen-activated extracellular signal regulated kinase; mTOR, mammalian target of rapamycin; PAK4, p21 (RAC1) activated kinase; RAF, rapidly accelerated fibrosarcoma; SYNE1, Spectrin repeat containing nuclear envelope protein 1; TAF1L, TATA-box binding protein associated factor 1 like; TGF, transforming growth factor; TP53, tumor protein 53; Wnt, wingless related integration site.

1.2.3 Gene mutation involved in the pathogenesis of colorectal cancer

1.2.3.1 RAS mutations

The EGFR is a proven pathological targeting pathway in CRC. Thus the MAPK pathway act as a downstream signal, and such changes play a significant role in patient classification for matching treatments. K&NRAS (RAS) variants are viewed as different biomarkers because they can be discovered across both hyper and nonhypermutated data and exhibit a fully exclusive trend. [93]. KRAS regulates cellular mechanisms like the RAS-RAF-MAPK, PI3K-Akt, and RAS-GEF signaling pathways, which are connected to cell growth and cytokine production [94–96]. Consider the Ras/Raf/MAPK signaling pathway as an example. When an extracellular ligand binds to the transmembrane EGFR in response to excitation of the receptors like tyrosine kinase is activated. The determination of K&NRAS variants, particularly changing exons 3 & 4, in tumor biopsies or circulating tumor DNA (ctDNA), in approximately 50% of patients suggested that the primary cause of tolerance is a clonal choice that occurs under the strain of treatment [97–100].

1.2.3.2 BRAF mutation

A significant indicator of a poor prognosis in CRC is the BRAF V-600/E type of gene mutant. 4 In over 50% of initial CRC samples, primarily in right tumors, it co-occurs with MSI. Only 24% of BRAF V600E-variant patients have interacted with MSI in the metastatic situation because the consequences of recurrence for MSS BRAF-variated CRC are substantially more than those globally [101]. It’s interesting to note that left-sided MSS tumors frequently have the highly uncommon BRAF nonV600 mutations, as shown in Table 1.1, mainly codons 594 and 596, which don’t seem to be associated with bad outcomes [106]. Anti-EGFR & BRAF V600E genetic changes Modest results show that cetuximab and panitumumab had almost no impact or just a negative impact on the continued existence of the BRAF V600E-altered population, suggesting the ab therapy is still not sufficient to alter practise [107] in the subsequent treatment lines [108].

Table 1.1

1.2.3.3 PIK3CA and PTEN mutations

Primary resistance to targeted therapy also appears to be conferred by molecular changes in additional EGFR pathway nodes. These include loss of PTEN, which usually coexists with RAS variations, and triggering alterations in exon 20 of this mutation, suggesting cross-connection to resistance to anti-EGFR mAbs [102]. Whether PIK3CA or PTEN gene changes can be treated in a therapeutic context is still debatable. Early clinical trials using matching PI3K pathway inhibitors on groups of cancer patients with PIK3CA or PTEN variants, as shown in Table 1.1, did not show any effectiveness. First-line PI3K-targeted medication susceptibility in CRC is probably caused by co-occurring MAPK pathway mutations [103,104].

1.3 Diagnosis for colorectal cancer

Endoscopy is the most widely used and effective procedure for diagnosing CRC [109,110]. It contains colonoscopies and sigmoidoscopies. These tests enable one to pinpoint the tumor’s location and remove a portion of the large intestine for histological analysis. The sigmoidoscopy’s specificity and sensitivity for detecting polyps and expanded CRCs are 92%–97%. Only the rectum and bottom portion of the colon can be seen during a sigmoidoscopy. Having comparable sensitivity and specificity, a colonoscopy enables the acquisition of a picture of the entire intestine [111,112]. Noninvasive virtual colonoscopies are being used increasingly regularly lately. By using computed tomography and obtaining a three-dimensional image of the large intestine concurrently, it is possible. Virtual colonoscopy reduces the possibility of problems related to large intestine puncture or hemorrhage [109,113]. According to Grossetto et al., periodic assessment of CRC patients or other neoplasms that have metastasized to the liver, together with FDG-PET/CT [114], has a significant effect on determining the disease’s stage and selecting candidates for isolated liver metastasis excision. Metabolism of g Glucose in 18F-FDG-PET/CT is not influenced by variance in tumor volume, and tumor alteration before and after therapy is unrelated to morphological changes in the tumor. Individuals with advanced colon cancer may be monitored for chemotherapeutic therapy with 18F-FDG-PET/CT [115].

Fecal occult blood testing is a quick, inexpensive, and noninvasive diagnostic procedure. As a result of the test, hemoglobin is found in the stool, which is a sign of stomach bleeding, as shown in Table 1.2. Additionally, blood in stools is a general sign of CRC since it can result from polyps larger than 1–2 cm in diameter in addition to malignant alterations [118]. When repeated, the test’s sensitivity can rise by up to 90% [119]. The immunohistochemistry fecal occult blood test (FIT), also used in CRC diagnostics [120], identifies human globin, a protein that works with heme to form hemoglobin. Molecular detection techniques, such as sDNA, are being used to detect DNA alterations in colorectal adenocarcinomas. Since the DNA in feces is stable, it can be isolated and distinguished from the DNA of bacteria [117]. Genetic and epigenetic assays alone have limited utility in diagnosing CRC. It is not frequently offered, and the costs are expensive [121]. The lack of efficacy of molecular diagnostics for CRC drives the quest for alternative, less expensive biomarkers found in biological matter.

Table 1.2

1.4 Treatment for colorectal cancer

CRC remains the second-most common cause of cancer-related worldwide, despite improvements in surgical methods, chemical therapy, and radiation therapy. Endoscopic procedures are used to diagnose early-stage CRC, like ESD and EMR. Lymph node excision, however, is an important part of surgical intervention since lymph node metastases in late-stage cancer are so common [122].

1.4.1 Endoscopic treatment

The need for minimally invasive procedures has increased, and the indications for endoscopic procedures have been broadened due to developments in the creation of flexible endoscopes and endoscopic instruments [123]. After diagnosis, T1 CRC may undergo endoscopic mucosal and submucosal resections in an en-bloc fashion for big and difficult lesions. Rectal lesions with extensive fibrosis have recently undergone perianal endoscopic myectomy, in which the layers of muscle are segmented into innermost circular and from outside longitudinal layers [124]. When performed by qualified endoscopists, endoscopic deletion is less risky and costly than the surgical method [125]. In situations where endoscopic resection is tough, or problems are very likely to occur due to many polyp-specific variables, including volume, position, shape, and motile character, CELS can drastically decline the expenses and risk of complications while maintaining participants’ colon [125].

1.4.2 Chemotherapy

Adjuvant and neoadjuvant chemotherapy, and instances that are difficult to treat the three main treatment categories for CRC chemotherapy. The following are examples of frequently utilized anticancer medications that are authorized to be used in therapies of CRC: Good examples of chemotherapeutic drugs comprise UFT, UFT +Ca-fnt, Cpb, Irtn, HCl-H2O, Oxptn, and FTD/TPI. The preceding drugs focus on specific molecular events: BEV, RAM, AFL, CET, PANI, REG, Ecf, and Bmt [126].

1.4.3 Radiotherapy

Radiotherapy service users with advanced or metastatic rectal cancer are treated with radiation therapy as adjuvant treatment after surgical intervention repetition or before surgical procedure to minimize tumor quantity and maintain the anal sphincter. Furthermore, hospice care alleviates signs and prolongs survival for unresectable CRC patients with symptomatic nodules [127].

1.4.4 Targeted therapies

Agents that target specific biological characteristics of tumors instead of those that kill cells by inhibiting cell division, encompassing both cancer cells and other types of cells, are referred to as targeted therapies. The balance between eliminating tumor cells and side effects such as damage to bone marrow and epithelial cells should be optimized by selectively inhibiting a dominant pathway. Regrettably, even though the RAS pathway is prominent in 40%–50% of participants with mCRC10, there are a variety of mutations in the RAS family that may accelerate the development of cancer in a given patient. In light of this, for instance, the enthusiasm immediately generated by new drugs has a suppressive impact on a preclinical mCRC model with K-RAS-12C mutation [128]. That is confirmed in clinical studies; the impacts will probably only affect about 4% or so of the individuals for whom the tumor has such particular alteration [129]. A humanized IgG and mAb that targets VEGF-A is called bevacizumab. It is restricted for use due to adverse effects such as GI perforation, bleeding, proteinuria, arterial thromboembolism, and impaired wound healing [130].

Ziv aflibercept has been completely humanized, miscible proteomics [130]. Its approval, coupled with FOLFIRI in application of the second line, focuses on phase III blind VELOUR studies [131] allocated by the person who had previously had 0xaliplatin to undergo Folfiri and a placebo. The extracellular domain of the EGFR-2 is the target of fully human IgG1 mAb ramucirumab [132]. It results in side effects like mucositis, hypomagnesemia, paronychia infections, skin fissuring, and acneiform rash [130].

1.5 Recent advances in the therapeutic interventions of colorectal cancer

The utilization of RAS-type gene alterations, anti-BRAF precise approaches, and microsatellite instability as high clinical indicators using immune checkpoint inhibitors is now the fundamental basis of therapeutic principles in mCRC. Personalized medicine appears to be the big, audacious objective that the future in all the key branches of medical oncology is heading towards. The next-generation sequencing trend is the subject of extensive research [133] (Table 1.3). The COLOMATE umbrella case is a fascinating ongoing study that detects colorectal tumor cfDNA and assigns patients suffering from advanced CRC to target intervention groups based on the genetic characteristics of their tumors. It seems to use the genetic material modeling shown in Table 1.3. The idea that this strategy might replace our current clinical practice in the not-too-distant future is interesting. Here are a few fresh targets that, in our opinion, could herald imminent innovation: ALK, ROS1, ALK, PI3K, NTRK fusions, RET, FGFR, and PI3K [135].

Table 1.3

1.6 Conclusion

Analysis of the diverse yet connected molecular mechanisms implicated in CRC with a key focus on ligand–target interactions was discussed in this chapter. The assessments for the genes that significantly impact the progression of the disease were also highlighted for their relevance in the progression of this cancer form. Like other cancers, protein kinases involved in CRC have seen much focus and committed efforts due to their crucial role in subsidizing, inhibiting, or changing the disease course. Patients of CRC most benefitted from anti-EGFR mAbs. This population is especially vulnerable to such pathway blockage or dual EGFR inhibition in preclinical studies and is already in drug trials coupled with MEK antagonists. In the present context, the evaluation of CRC is motivated, especially by the treatment’s ongoing development. Although much more experts are accepting that unique biomarkers therapy and diagnosis are supposed to add change in perspective, this is waiting to gain momentum. Moreover, this carcinoma is expanding rapidly, mandating various combination tactics to get beyond its therapeutic limitation. In a broad sense, researchers are not only motivated by the fact that CRC patients might have longer life expectancy with a diverse array of therapeutic targets, but also they anticipate much more individualized treatments to be developed that promote even longer survival with fewer adverse drug reactions and have the possibility for complete recovery. Remarkably, a course of acquaint with inhibitors for numerous mechanisms and conformational cancer targets is being found using developments in immersive drug development models and algorithms that save effort, cost, and labor. Hence, it can be anticipated that the advancements in biomarker–drug combinations will keep moving from the genomic to the gene expression level with the identification of a common understanding of molecular subtypes. Further, our increased understanding of the pathways involved in progressing CRC, such as dependence on transforming growth factor signaling and other related pathways, will be more elaborate. All these new paradigms of targeted therapeutic and diagnostic approaches might finally lead to an enhanced likelihood of eradicating CRC in its early stages.

Abbreviations

Ab Antibody

AKT Ak strain transforming

APC Adenomatous polyposis coli gene

Bmt Binimetinib

BVAb Bevacizumab

C-MET cellular-mesenchymal-epithelial transition factor

Ca-fnt calcium folinate

CELS Combined endoscopic and laparoscopic surgery

CK I Casein kinase I

Cpb Capecitabine

CRC Colorectal cancer

CTAb Cetuximab

DCC Deleted in colon cancer

Ecf Encorafenib

EGRF Epidermal growth factor receptor

EMR Endoscopic mucosal resection

ErbB Erythroblastosis oncogene B

ERK Extracellular signal-related kinase

ESD Endoscopic submucosal dissection

FAP Familial adenomatous polyposis syndrome

FDG PET/CT Fluorodeoxyglucose positron emission computed tomography

FIT Fecal Immunohistochemical test

FOBT Fecal occult blood test

GIT Gastrointestinal track

GSK-3 Glycogen synthase kinase 3

HCl H2O hydrochloride hydrate

HER Human epidermal growth factor receptor

HGF Hepatocyte growth factor

HIF Hypoxia inducible factor

HNPCC Hereditary nonpolyposis colorectal carcinoma

IRS2 Insulin receptor substrate 2

Irtn Irinotecan

JAK Janus kinase

LarIb Larotrectinib

MAPK Mitogen-activated protein kinase

MCC Mutated in colon cancer

MDM2 Mouse double minute 2 homolog

mTOR Mammalian target of rapamycin

NAT N-acetyltransferase

NSCLCs Nonsmall-cell lung cancers

NTRK Neurotrophic tyrosine receptor kinase

ONIb Onvansertib

ORR Overall response rate

Oxptn Oxaliplatin

PAK4 p21 (RAC1) activated kinase

PCP Planar cell polarity

PDGF Platelet-derived endothelial cell growth factor

PEMAb Pembrolizumab

PIP2 Phosphatidyl-inositol-bisphosphate

PIP3 Phosphatidylinositol (3,4,5)-trisphosphate

PIP3K Phosphatidylinositol 3-kinase

PKB Protein kinase B

RAS/RAF Rapidly accelerated fibrosarcoma

SOSs Son of sevenless homologs

STAT Signal transducer and activator of transcription 3

TRAb Trastuzumab

TUIb Tucatinib

UFT tegafur uracil

VAIb Vactosertib

VEGF Vascular endothelial growth factor

VEGFR Vascular endothelial growth factor receptor

Wnt Wingless related integration site

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