The Impact of Metformin Administration on the Clinical Outcome of Stage IV Colon Cancer

Colon cancer is significant Public health problem and one of the most common cancers worldwide. With Annually, more than 1.36 million patients are diagnosed with this disease. Approximately, 694,000 colon cancer - associated mortalities Occur per year accounting for 8.5% of all cancer-related deaths and making colorectal cancer (CRC) the third most common cause of death.

Multiple risk factors for colon cancer were identified including increasing age, smoking, black race, obesity, low fiber and rich processed food diet or as so called western diet, insulin resistance, obesity, type 2 diabetes and the metabolic syndrome. (Kaneko et al.,2014).

Increased body weight and type 2 diabetes have been linked to many types of cancer. This association has primarily been attributed to insulin resistance and cluster factors of metabolic syndrome thought to also play additive carcinogenic roles. (Inoue and Tsugane, 2012). Diabetes, in specific, has been proposed as a risk factor for many cancers, including colon, breast, prostate, kidney, and pancreatic cancers (Giovannucii et al, 2010), (SteinmausC et al, 2011). Insulin resistance in patients with diabetes can pro-mote tumorigenesis by increasing the levels of insulin-like growth factor 1, steroidal sex hormones, and inflammation (Jaiving M, 2010). In addition, the So-Called-Western diet, rich in processed foods and meats, sedentary lifestyle and obesity are may be mediated by hyperinsulinemia. (Inoue and Tsugane, 2012).

Glucose, The Co- factor in all risk factors, is one source of energy for tumor cells to support its growth and proliferation. Tumor cells depend on the intake of amino acids such as glutamine. Glucose uptake is regulated by growth factor signaling in normal on-proliferating cells. Activation of growth factor receptors stimulates changes in intracellular signaling, which in turn modifies metabolic pathways in support of proliferative growth. Hyperglycemia is often wrongly implicated as the sole source of cancer nutrition in patients with diabetes, when in fact cancer cells can thrive using other energy sources promoted by genetic mutations and aberrant intracellular signaling (Handelsman et al., 2013). Insulin has been shown to affect the growth of both normal and neoplastic epithelial cells and to have the capability of promoting mitosis in vitro, directly or indirectly via Insulin-like growth factor 1 (IGF-1). It has been proposed that insulin and insulin-like growth factors may be involved in colon carcinogenesis (Trevisan et al., 2001), Aleksandrova et al., 2011). Insulin acts as a growth factor, and insulin receptors are present in normal and malignant colorectal cells. This action would be potentiated by hyperglycemia which induces the secretion of insulin (Trevisan et al., 2001). That was proven through Several studies have shown that abnormal glucose metabolism is associated with an increased risk of colon cancer (Khaw et al., 2004; Hsu et al., 2012).

The primary treatment of colon cancer in several stages is to surgically remove part of the colon or all of it (colectomy). however, most cases need chemotherapy after surgery to improve the likelihood of being cured especially if colon cancer has spread to nearby lymph nodes. Radiation therapy is also available after surgery, but it mainly does not improve cure rates in people with colon cancer, And more frequently for people with rectal cancer. In patients with stage III colon cancer, the addition of oxaliplatin to a regimen of 5-FU and LV is known as FOLFOX, which has become the adjuvant gold standard therapy. As for patients have not received any previous chemotherapy for metastatic disease, several studies were made where the expert opinion is that chemotherapy FOLFOX or CAPOX is recommended. (Goldberg, R. M. (2006) Metformin is known as a hypoglycemic agent that regulates glucose homeostasis by inhibiting liver glucose production and increasing muscle glucose uptake. In addition, it's the first line oral therapy used in the treatment of type II diabetes. During the past decade, there has been an increasing interest in the relationship between metformin and Colon cancer, including Onset and prognosis. In some studies, metformin may have anticancer effects both in vivo and in vitro settings Various mechanisms have been proposed for the anticancer effects of metformin. Several basic studies have demonstrated that metformin inhibits cancer cell proliferation, metabolism and angiogenesis by activating adenosine monophosphate-activated protein kinase (AMPK). AMPK plays a critical role in maintaining cellular functions under energy-restricted conditions. Activated AMPK inhibits the synthesis of glucose, lipids, proteins, and cell growth under general conditions (Dowling RJ, 2007), (Zakikihani M ,2006). It also, inhibits mTOR (mammalian target of rapamycin) signaling, subsequently inhibiting protein synthesis and cell proliferation, which may be a direct mechanism driving metformin-mediated suppression of cancer cell growth. Several other anticancer mechanisms have been proposed, including inhibition of serum insulin and insulin like growth factor 1 levels (Kalaany NY,2009) that In states of insulin resistance, works in the liver by lowering systemic glucose levels and improving secondary hyperinsulinemia, preventing the latter's effects on tumor growth and progression (Pollak MN , 2012 ) , downregulation of cyclin D1 protein expression(Bensahra I,2008), activation of apoptotic pathways (Isakovic A , 2007) , reversing the effects of the high-energy diet in promoting the growth of colon cancer by inhibiting expression of fatty acid synthase (Algirec , 2010) Although several mechanisms have been identified, it is necessary to determine other unknown antitumor mechanisms of metformin to identify appropriate cancer targets. A recent study, found that metformin treatment reduced interleukin 6 (IL-6) inflammatory, and epithelial mesenchymal transition (EMT) signaling using high-throughputdata, and then test the mechanism experimentally through human cell lines invitro (Kang et al, 2018). However, a study about metformin effect on IL-6 pathway clinically have never been addressed.