The authors have declared that no competing interests exist.
Colorectal cancer is one of the most common malignancies encountered in the western world and is now the third most common cause of cancer related mortality
Research into the molecular mechanisms has led to advances in therapies targeted at various molecular pathways
In this review, a brief survey of the various molecular pathological mechanisms underlying colorectal carcinogenesis is presented. In the context of this approach, the response of patients to the various therapies is described. A brief description of the novel approach of molecular pathological epidemiology is also presented.
A pubmed search was performed for relevant literature using the terms colorectal cancer, chemotherapy, molecular biology colorectal cancer, monoclonal antibodies, colorectal cancer genetics, pharmacogenetics of colorectal cancer. The bibliographies of the retrieved papers were also searched for articles of relevance.
Histological observations indicated that colorectal malignancies develop via a worsening degree of dysplasia of normal colonic mucosa
Carcinoma model of carcinogenesis which has undergone various modifications as precise molecular
Details have been elucidated
The CIN pathway is identified by aneuploidy and structurally altered chromosomes and is associated with deletions in chromosome 5, 18q or 17q
The CIMP pathway results from the silencing of tumour suppressor genes by the hypermethylation of cpg islands within the promoter regions of these genes with a concomitant global DNA hypomethylation
Defects in the DNA mismatch repair (MMR) system result in the accumulation of mutations in repeat sequences known as microsatellites and are the first steps along the MSI pathway
The recently recognised serrated pathway describes the progression of traditional serrated adenomas (TSA) and sessile serrated adenomas (SSA) to adenocarcinomas
There are various other mutations, particularly in signalling pathways that can also predispose to malignant transformation and act in conjunction with the above mentioned pathways. These are usually pathways involved in cellular proliferation or apoptosis and the mutation can result in a constitutive activation of the pathway which favours proliferation. Many of the genetic abnormalities result in overlapping dysregulation of molecular pathways and are not mutually exclusive
The diverse biological roles of the EGFR pathway are reflected in the different downstream pathways it can activate. Pathways known to be activated by EGFR ligand binding are the RAS- RAF-MAPK pathway, PI3K pathway and the protein serine/throenine kinase Akt pathway
Components of the TGF-b pathway also act on the RAS-RAF-MAPK pathway, PI3K/Akt pathway
Overlapping with the EGFR pathway and therefore these mutations tend to have a synergistic
Effect
The role of p53 in a variety of carcinogenic pathways has been reported and it has been noted in Almost 50% of colorectal cancers worldwide
The considerable amount of research conducted into the molecular aetiology of colorectal cancer has led to the development of therapies that have increased survival rates among patients 45. Despite these improvements, a clear understanding of which patients would respond to and benefit from these therapies is still lacking. Research is ongoing in terms of identifying predictive molecular markers that would help identify patients who would benefit from such therapies rather than surgery alone.
5-Fluorouracil (5-FU) which is administered intravenously has been used as first line chemotherapy in the adjuvant setting for colorectal cancer for decades. Capecitabine, which is an oral fluoropyrimidine is a prodrug which gets converted to a 5-FU following enzymatic conversion
Various studies have been done that have looked at how the levels of the various enzymes involved in the metabolism of the fluoropyrimidines relate to response rates. However, many of these studies have given conflicting results due to the difference in methodology and patient population. Ciaparrone et al demonstrated a correlation between a low level of DPD determined by immunohistochemistry (IHC) and RT-PCR with prolonged overall survival and disease free survival whereas no such correlation was seen in a study by Westra el al
UP is a key enzyme in the conversion of 5-FU to its active metabolite and therefore it would be Expected that a high level of UP would correlate with greater effectiveness. This has been Demonstrated in vitro by Mader et al
TS which is a target of fluoropyrimidines is necessary for DNA synthesis and repair and therefore low levels of TS can lead to the accumulation of DNA damage. However, despite malignant cells being more proliferative than non malignant cells, a lack of TS also results in a lack of DNA synthesis. This implies that TS deficient tumours tend to be less proliferative. While in vitro studies demonstrate a positive correlation between TS levels and 5-FU responsiveness, in vivo studies are inconclusive
Irinotecan mediates its action via the inhibition of topoisomerase 1 (topo-1). Topo-1 plays an important role in DNA replication by relaxing the supercoiled DNA helix by the introduction of single stranded breaks
In vitro studies have demonstrated an increased responsiveness to irinotecan in cell lines with higher topo-1 activity. A study by Braun et al showed that in patients expressing higher levels of topo-1 determined by IHC, a major overall survival benefit was seen with the use of irinotecan or oxaliplatin compared to patients on 5-FU
Both CES1 and CES2 are expressed in hepatocytes and malignant colon cells
Oxaliplatin is a third generation platinum compound which is notable for its anti-tumour activity in colorectal cancers and its synergistic action with other chemotherapeutic agents such as irinotecan and 5-FU
Intracellular levels of oxaliplatin are determined by the relative rates of uptake and efflux. Various uptake and efflux transporters have been identified such as organic cation transporters (OCT), copper efflux transporters and P-type atpases ATP7A and ATP7B. These transporters may play a role in determining the sensitivity to oxaliplatin
The MMR system, despite its role in DNA repair, does not appear to play much of a role in determining the response to oxaliplatin. Rather, a different pathway known as the Nucleotide Excision Repair (NER) pathway is what is involved in the excision and repair of DNA-platinum adducts
On a theoretical basis alone, one would expect a high sensitivity to oxaliplatin if there is a deficiency in the NER pathway. Studies have been done looking at the levels of ERCC1 and oxaliplatin responsiveness which indeed do suggest this relation
Monoclonal antibodies target specific molecules in specific carcinogenic pathways. The issue of predictive biomarkers is particularly important when it comes to monoclonal antibody therapies as these are very expensive and used only in advanced or metastatic cancer. The two pathways targeted by monoclonal antibody therapies in clinical use are the vascular endothelial growth factor (VEGF) pathway and the EGF pathway.
VEGF, of which there are types A to E, is a potent pro-angiogenic factor and its importance is highlighted by the fact that neoangiogenesis is required for the survival and metastasis of all solid tumours beyond a certain size
Bevacizumab, which is a monoclonal antibody targeted against VEGF-A has been shown to be more effective when used in conjunction with another cytotoxic agent and its use has been approved in the United States as first line treatment of metastatic colorectal cancer. The improvement noted when it is used in combination has been hypothesised to be due to the destruction of the peripheral vasculature of the tumour resulting in the remaining vasculature becoming more organised. This would lead to an improved delivery of the cytotoxic agent used in combination
Larger studies need to be performed to identify and validate predictive biomarkers for bevacizumab. In a study of 40 patients with metastatic cancer, Ronzoni et al demonstrated a significant correlation between the levels of total and resting circulating endothelial cells (tcec, rcec) and the antitumor efficacy of bevacizumab
Cetuximab and panitumab are two different monoclonal antibodies targeted at the EGF receptor (EGFR). These agents have been demonstrated to be effective either as part of a combination therapy regimen or as single agents. The observation that these agents are only effective against a minority of patients with metastatic disease highlighted the need for predictive biomarkers
Despite the biological rationale, only a small proportion of patients with an unmutated KRAS gene respond to anti-EGFR therapy indicating that there could be other predictive biomarkers
The PI3K pathway is also activated by EGF and therefore its role as a potential predictive marker
Is the subject of much research. Several small studies have associated mutations in this pathway with a resistance to anti-EGFR therapy, however since these mutations can coexist with BRAF or KRAS mutations, its importance is unclear
Chronic inflammation is known to be associated with a predilection towards malignant transformation and is evidenced in the higher incidence of colorectal cancer in patients with inflammatory bowel disease (IBD)
COX has also been demonstrated to promote angiogenesis by activating angiogenic factors such as vascular endothelial growth factor (VEGF) via the action of PGE2 . In fact, clinical studies have demonstrated reduced mortality from colorectal cancer with aspirin use and this benefit seems to be stronger with prolonged use. The benefit seems to be limited to cases of sporadic cancer only and not colorectal cancers of a hereditary aetiology such as those with FAP or Lynch syndrome
Recent research by Liao et al has demonstrated a better prognosis for colorectal cancer with aspirin use in patients with mutations in PIK3CA
The new field of molecular pathological epidemiology is leading to a paradigm shift that not only applies to colorectal cancer but also to various other malignant and benign pathologies.The fundamental premise of this approach is the unique disease principle which posits that each patient’s pathology results from the interaction of heterogeneous biological and environmental factors that include genetic mutations, inter cellular communication, microbial presence and exposures derived from the patient’s lifestyle and environment
This is an interdisciplinary field and draws on subjects such as molecular biology, epidemiology, statistics and bio informatics. The driving force behind the natural evolution of this discipline has been the desire to develop personalised medicine. One of the noteworthy successes of this approach in colorectal cancer had been the identification of PIK3CA mutations as a potential biomarker to determine a patient’s response to aspirin
Despite the logical appeal to this approach, there are challenges ahead in the form of social, economic and healthcare disparities. How such disparities can be effectively incorporated into a single theory to produce a workable model should remain the focus of researchers as such a theory would then be best suited to address not only diseases such as colorectal cancer but also other pathologies that would in due course become widespread around the world.
The last few decades have led to a considerable understanding of the underlying molecular processes of malignant transformation in colorectal tissue. Our understanding has come a long way from the initial adenoma-carcinoma model and it is possible that in the future, the details of new carcinogenic pathways would be elucidated. All this would aid towards the development of personalised medicine and new therapeutic modalities as more molecular targets are identified. The identification of responders to specific therapies would not only result in lower costs, but would also be able to minimise the exposure of the patient to undesirable side effects.