Colorectal Cancer Review (CRC) - Assay Genie

Carcinogenesis is a multi-step process that develops through epigenetic changes and mutation of multiple genes, including loss of function of tumour suppressor genes and gain of function of oncogenes. These genetic changes in normal cells can each contribute a growth advantage, leading to the transformation of cells into cancer cells [1]. In 2000, Hanahan and Weinberg described a series of 6 biological capabilities or ‘hallmarks’ acquired by most types of cancers during the multi-step development of cancer (Figure 1). They are as follows; ‘sustaining proliferative signalling’, ‘evading growth suppressors’, ‘activating invasion and metastasis’, ‘inducing angiogenesis’, ‘resisting cell death’ and ‘enabling replicative immortality’ [2].

In 2011, Hanahan and Weinberg went on to describe two additional ‘hallmarks’ of cancer. These were ‘deregulating cellular energetics’ and ‘avoiding immune destruction’ (Figure 1). Acquisition of these capabilities is enabled by genomic instability, that is important for the generation of the genetic diversity that promotes their acquisition [3]. As well as genetic instability, a second enabling characteristic is tumour-promoting inflammation, which refers to the ability of the tumour to harness the inflammatory response to promote tumorigenesis.

Figure 1: The ‘hallmarks’ of cancer. The hallmarks of cancer are biological functions acquired during the development of tumours. They include; sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis and activating invasion and metastasis. The two most recently described hallmarks of cancer are reprogramming of energy metabolism and evading immune destruction. Enabling characteristics such as genomic instability allow cancer cells to generate mutations that enhance tumour progression. The immune response used to protect against pathogenic insult can facilitate tumour promotion by activating proliferation and metastasis. Figure adapted from D Hanahan and R. Weinberg, Hallmarks of cancer: the next generation, Cell 2011.

Adenocarcinoma of the colon and rectum (colorectal cancer (CRC)) is the third most common cancer worldwide, with over 1.4 million people diagnosed each year [4]. 1 in 5 CRCs have a familial or congenital gene mutation that compounds colon cancer risk and these cancers usually become established at a young age. Hereditary non-polyposis colorectal cancer (HNPCC) accounts for approximately 5% of these cases and familial adenomatous polyposis (FAP) accounts for ~1%. The genetic mutations responsible for these two conditions lie in the mismatch repair genes and in the adenomatous polyposis coli (APC) gene, respectively. The remaining ~80% are sporadic, with no clear genetic origin. They usually occur at an advanced age. This suggests that environmental factors may cause genetic mutations that accrue over time.

The risk of developing cancer depends on many factors. Those with a parent, sibling or child with the disease have a 2-fold increased risk of developing the disease [5]. Other risk factors include family history, increasing age, the presence of colonic polyps, inflammatory bowel disease (IBD) and a previous history of colon, ovarian or breast cancer. Environmental factors such as smoking, alcohol, viral exposure, exogenous oestrogens, a low fibre diet and physical inactivity have also been identified as important risk factors for developing colon cancer.

Colon cancer development normally follows a measured gradient process, in which various genetic mutations gradually accumulate over time, inducing the transformation of healthy cells into cancerous cells. In the majority of cases, this malignant disease begins as a benign adenomatous polyp, which then develops into an advanced adenoma with high grade dysplasia. This is followed by progression to carcinoma and ultimately to metastasis (Figure 2). This process normally takes decades (Figure 2) [6].

Figure 2: Sequential morphological changes involved in CRC development. Hyper-proliferation of the epithelium is observed in the early stages of adenoma development. Initially, small adenomas form. Once severe dysplasia occurs, this marks the progression from early to late adenoma. The next sequential step is the progression from late adenoma to malignant carcinoma. During this transition increased vascularization and recruitment of immune cell populations are observed. This is followed by metastasis. Common alterations in genes and pathways associated with each stage of the transformation of normal epithelium to carcinoma are illustrated

Different genetic mutations have been shown to be associated with the various stages of colon cancer development (Figure 2). One of the earliest changes associated with CRC development is inactivation of the adenomatous polyposis coli (APC) tumour suppressor gene. APC is inactivated in the majority of sporadic CRCs, and is the genetic mutation responsible for colon tumour development in FAP [7]. Silencing of APC drives genomic instability and promotes cell growth as the cells are no longer bound by normal cell cycle checkpoints [8]. In many cancers, the RAS-GTPase family proto-oncogene K-RAS also becomes activated. This is usually linked with the transition from early to intermediate adenoma. The gene called deleted in colon cancer (DCC) can also be lost. This commonly occurs in the transition from intermediate adenoma to late adenoma. Mutations of the tumour suppressor p53 are associated with the development of carcinoma. Loss of chromosome 8p is associated with carcinoma to metastasis transition [9]. Other genes or pathways that are frequently mutated in CRC include the cyclooxygenase (COX) signalling pathway, the signal transducer phosphatidylinositol 3-kinase (PI3K), the Wnt/beta-catenin signal transduction pathway and the transforming growth factor (TGF)-β-signalling pathway [10-12].

Clinical staging of CRC is used to determine the extent of the cancer and involves the use of the Tumour/Node/Metastasis (TNM) staging system. The TNM system classifies the stages of colon cancer under the following headings: T-the degree of invasion of the intestinal wall; N-the degree of lymphatic node involvement; and M-the degree of metastasis. Stage I refers to CRCs confined to the mucosa or indicates lymph node metastasis and stage IV cancers are those that have metastasized to distant organs. The liver and the lung are the two most common sites of CRC metastasis [13].

Surgery alone is used to treat individuals with stage I or stage II CRC. Radiation therapy or chemotherapy may be recommended in stage III post-surgery. Most commonly 5-Fluorouracil (5-FU), lucovorin and oxaliplatin combined, or cappecitabine and oxaliplatin combined chemotherapy regimens are employed. In stage IV disease, chemotherapy may be employed pre-surgery to shrink tumours and also post-surgery to remove any remaining cancer cells not removed by surgery. At this stage, targeted therapies may be employed alone or in combination with the previously mentioned chemotherapy regimens. Targeted therapies include Cetuximab and Regorafenib which target the EGFR and VEGFR respectively. Radiation therapy is also used in Stage IV to relieve symptoms [14]. The 5-year survival rate for patients with stage I colon cancer is approximately 92% and this drops dramatically to ~11% for patients with state IV or metastatic disease [15].

References

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