Boster Pathways-> Cancer & Stem Cells

Colorectal Cancer Metastasis Pathway

Metastasis is the major cause of death in patients with colorectal carcinoma (CRC). The most common sites of metastasis are the liver and the peritoneum.

Overview of Colorectal Cancer Metastasis Pathway

Colon cancer is a malignant tumor that begins in the large intestine (colon). The colon is the digestive tract's final section. Colorectal cancer is the third most common type of cancer in the Western hemisphere, with an increasing incidence as people age. Colorectal cancer is caused by environmental and genetic factors that promote the acquisition of cancer-specific behaviors in colon epithelial cells.

Numerous studies have demonstrated that the majority of early neoplastic lesions in the colon (namely, aberrant crypt foci, adenomas, and serrated polyps) lose genomic and/or epigenomic stability, which is likely a critical molecular and pathophysiological event in the initiation and formation of colorectal cancer.

Mechanism of Action

Currently, two distinct sequences ranging from normal colon to colorectal cancer have been identified. Both sequences involve the progression of normal colon epithelial cells to aberrant crypt foci, followed by early and advanced polyps, and finally advanced cancer. The 'traditional' or 'classic' path (top) involves the development of tubular adenomas that can progress to adenocarcinomas. An alternate pathway (bottom) has been described in the last 5–10 years that involves serrated polyps and their progression to serrated colorectal cancer. Each sequence contains genes that have been mutated or altered epigenetically. Certain genes are shared between the two pathways (for example, KRAS), while others are distinct (such as BRAF).

The progression of colorectal cancer is mediated by a number of well-defined genetic alterations, including mutations in APC, BRAF, KRAS, PIK3CA, p53, and FBXW7. We present several key targets involved in the mechanism of colorectal cancer in this section, including:

APC (adenomatous polyposis coli)

The function of APC (adenomatous polyposis coli) has been linked to the Wnt signaling pathway. APC can degrade -catenin and promote cellular adhesion, migration, and apoptosis under normal conditions. Due to the fact that APC deficiency is sufficient to initiate tumor development, APC mutations impair -catenin degradation, while truncated APC fragments promote colorectal cancer cell migration and induce chromosomal instability.


KRAS (Kirsten rat sarcoma viral oncogene homolog), a small GTPase involved in intracellular signal transduction and a member of the MAP kinase (MAPK) pathway . KRAS mutations contribute to KRAS protein activity deregulation, resulting in the loss of GTPase activity and the acquisition of oncogenic activity. Malignant transformation is caused by point mutations in exons 2 and 3 of the KRAS gene. Around 37.4 percent of Iranian patients with colorectal cancer have KRAS mutations.


SMAD4 (SMAD Family Member 4), alternatively referred to as mothers against decapentaplegic homolog 4, is an extremely conserved protein found in all metazoans. It is a member of the transcription factor family SMAD, which acts as a mediator of TGF- signal transduction. Loss of SMAD4 protein expression has been reported in 9 percent to 66 percent of colorectal cancers (9.3 percent, 14 percent, 66 percent), and it is a common feature of early-onset colorectal tumors, as well as colorectal cancers diagnosed in other age groups

F-box and WD repeat domain-containing 7 (FBXW7)

FBXW7 (F-box and WD repeat domain-containing 7), a member of the F-box family of proteins, is a subunit of the ubiquitin ligase complex formed by Skp1, Cul1, and F-boxprotein (SCF). It may act as a tumor suppressor by regulating the ubiquitination and proteolysis of a variety of targets, including cyclin E. c-Jun, c-Myc, and Notch