Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review)

Abstract

Colorectal cancer (CRC) is the third most frequently detected type of cancer, and the second most common cause of cancer‑related mortality globally. The American Cancer Society predicted that approximately 147,950 individuals would be diagnosed with CRC, out of which 53,200 individuals would succumb to the disease in the USA alone in 2020. CRC‑related mortality ranks third among both males and females in the USA. CRC arises from 3 major pathways: i) The adenoma‑carcinoma sequence; ii) serrated pathway; and iii) the inflammatory pathway. The majority of cases of CRC are sporadic and result from risk factors, such as a sedentary lifestyle, obesity, processed diets, alcohol consumption and smoking. CRC is also a common preventable cancer. With widespread CRC screening, the incidence and mortality from CRC have decreased in developed countries. However, over the past few decades, CRC cases and mortality have been on the rise in young adults (age, <50 years). In addition, CRC cases are increasing in developing countries with a low gross domestic product (GDP) due to lifestyle changes. CRC is an etiologically heterogeneous disease classified by tumor location and alterations in global gene expression. Accumulating genetic and epigenetic perturbations and aberrations over time in tumor suppressor genes, oncogenes and DNA mismatch repair genes could be a precursor to the onset of colorectal cancer. CRC can be divided as sporadic, familial, and inherited depending on the origin of the mutation. Germline mutations in APC and MLH1 have been proven to play an etiological role, resulting in the predisposition of individuals to CRC. Genetic alterations cause the dysregulation of signaling pathways leading to drug resistance, the inhibition of apoptosis and the induction of proliferation, invasion and migration, resulting in CRC development and metastasis. Timely detection and effective precision therapies based on the present knowledge of CRC is essential for successful treatment and patient survival. The present review presents the CRC incidence, risk factors, dysregulated signaling pathways and targeted therapies.

Keywords: colorectal cancer; signaling pathways; mutations; metastasis; targeted therapy.

Figure 1

Map showing estimated age-standardized cancer incidence rates (worldwide) in 2018, colon and rectum, both sexes, all ages [reproduced from http://globocan.iarc.fr/ (31)].

Figure 2

(A) Anatomical subtypes of colorectal cancer and their associations with tumor molecular features and other factors. (B) Colorectal adenoma-carcinoma sequence. The APC mutation is the first step transforming normal colorectal epithelium to adenoma. The adenoma-carcinoma sequence is caused by three major pathways: CIN, MSI and CIMP. CIN, chromosomal instability; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; APC, adenomatous polyposis; KRAS, KRAS proto-oncogene GTPase; BRAF, B-Raf proto-oncogene serine/threonine kinase; TP53, tumor protein 53; LOH, loss of heterozygosity; HNPPC, hereditary non-polyposis colorectal cancer; MLH1, mutL homolog 1; MSH2, mutS homolog 2; DCC, DCC netrin 1 receptor; TGFBR, transforming growth factor-β receptor; BAX, BCL2 associated X apoptosis regulator; IGF2R, insulin like growth factor 2 receptor; CDC4, cell division control protein 4.

Figure 3

These pathways play an important role in cell growth, proliferation, and homeostasis, thus, a mutation in anyone may cause cancer cell survival, division and metastasis. These pathways include (from left to right) the PI3K/Akt pathway mutation linked with over-expression of Akt, causing cell division and the inhibition of apoptosis is reported in 70% of CRC cases. The JAK/STAT pathway is associated with pro-inflammatory gene expression due to binding and activation of GAS elements; EGFR/MAPK pathway regulates the CREB transcription factor, and over-expression of EGFR is reported in CRC cases; Wnt pathway regulates the β-catenin levels in the cell and activate target genes such as MYC, CCND1 and AXIN2. The Notch pathway and associated Notch-1 have been found to be upregulated in CRC and adenocarcinomas; SHH pathway mutations are reported in CRC (Smo, Gli1 and Ptc); the TGF-β pathway is 'lost' in cancer cells, thereby resisting growth inhibition; however, later stages of CRC report the pathway leading to EMT.

Figure 4

(Left to right) the p53 signaling pathway is activated in response to external stress (UV rays, hypoxia, etc.) and functions to repair DNA damage; the Hippo signaling pathway controls cellular homeostasis and proliferation; the Nrf2/KEAP1 signaling pathway is activated in response to ROS that damage cellular components; the TRAIL-mediated signaling pathway initiates extrinsic and intrinsic apoptosis of cells.

Figure 5

The various canonical and non-canonical signaling pathways interact with one another through downstream regulation or by inhibiting or enhancing the working of a gene/pathway. A few of these interactions have been shown in the figure inhibiting (dashed arrows) or inducing (black arrows) the working of the various components of the signaling pathways.