The role of IGF-1 in the development and progression of colorectal cancer
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Colorectal Cancer (CRC) is one of the most prevalent cancers among men and women in the world. Its presence is increasingly being felt in people who east a western diet. A sedentary life, lack of physical activity, and excessive consumption of red meat are some of the major risk factors associated with the disease. Furthermore, increasing correlations are demonstrating that diabetic and obese patients are at a higher risk of developing colorectal cancer. Of increasing interest is the presence of growth factors present in these individuals. One such growth factor, which is being crucially studied for the purposes of treatment and prevention, is insulin-like growth factor-1 (IGF-1.) IGF-1 is part of the IGF axis, an endocrine axis, composed of IGF-1 receptor (IGF-1R), numerous IGF binding proteins (IGFBPs), and insulin. Many studies have highlighted the high levels of IGF-1 in the blood of patients with CRC. However, currently IGF-1 is only regarded as a biomarker for CRC. The role that a dysregulated IGF axis plays in the development and progression of CRC is largely unknown. This review of the current literature has underlined major risk factors of colorectal cancers which are able to exert their unwanted effect through their impact on the IGF axis. These factors include obesity, diabetes, radiotherapy, and oxidative stress. The understanding of the dysregulation of IGF axis’ pathways in colorectal cancer is crucial for the development of new treatment options for the disease in the future. In this paper the known mechanisms through which IGF-1s binding to IGF-1R causes unnecessary cellular proliferation in colorectal cancer patients is discussed. IGF-1R is a dimer with a tyrosine kinase domain on the intracellular side. Ligand binding to this receptor causes autophosphrylation and the activation of the Phosphoinositide 3-kinase/Protein Kinase B/Wnt (PI3K/Akt/Wnt) pathway. The PI3K/Akt/Wnt pathway is known to cause cellular proliferation and, in excess, metastasis. The potential for the IGF axis to cause metastasis will also be discussed in more direct terms. Levels of IGF-1R and IGF-1 are positively correlated with different stages of metastasis. Furthermore, in vitro and in vivo studies have demonstrated that IGF-1 has the ability to increase lymphatic vessel density. The potential for changes in the treatment of patients with colorectal cancer and prevention of the disease in those who are at risk of it is also discussed. Currently the main therapies through which the IGF axis is targeted are chemotherapy and immunotherapy. However, these therapies can cause a lot of damage to the body as they are not specific to the cancer cells. A new theory known as the cancer stem cell theory is readily being used to design treatment options for the future. According to this theory, cancer stem cells are present in small amounts in everyone and are responsible for the relapse of cancer after radiation or chemotherapy. These cells are increasingly being targeted for drug design as they provide specificity which would, hypothetically, not produce as many side effects. Another mechanism, which provides specificity and is gaining popularity in treating CRC, involves the use of microRNAs. microRNAs are small RNAs which can bind to mRNAs of major genes and prevent their translation. miRNAs which suppress the genes of the IGF axis can be administered to the patient to specifically address the problem. Numerous such miRNAs have been discovered and their roles were discussed in further detail. Lastly, the ability of some bioactive compounds to perturb the IGF axis in CRC is also discussed. These compounds are mainly found in some of the fruits and vegetables, and spices like curcumin. Vitamin D is another dietary compound which has the potential to prevent CRC in the susceptible population. However the extent to which small amounts of these compounds can prevent CRC is largely indeterminate and there is a need to conduct studies on the compounds’ dosing regimen. The review of the literature on colorectal cancer has discussed some of the latest strategies in tackling the disease as well as providing mechanistic insights into IGF axis’ dysregulation in CRC.