New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets.

ABSTRACT
Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.

Introduction and epidemiology
Colorectal cancer (CRC) is the second and third most common type of cancer in females and males, respectively, with 1.24 million new cases diagnosed in 2008 alone.1 According to the Canadian Cancer Society, CRC has the third highest cancer incidence in both men and women.2 Countries with the highest incidence include those in Europe, North America, and Oceania, while the lowest incidence is found in some South and Central Asian countries and in Africa.3 In Saudi Arabia, CRC ranks first and third among males and females, respectively, of all cancers diagnosed in 2011.4 According to the latest data by the Iran National Cancer Registry (INCR), the age-standardized incidence rate of Iranian CRC patients is 11.6 and 10.5 for men and women, respectively. The overall 5-year survival rate is 41%, and the proportion of CRC among the younger age group is higher than that of Western countries.5 In developed countries, CRC occurrence is higher in nonsmokers of both males and females combined.6 In Europe, CRC is the second leading cause of death among all cancer types in both men and women.7 In the United States of America, CRC is the third leading cause of death and the 5-year overall survival (OS) of this disease is nearly 65%.

Seventy percent of CRC cases are sporadic with the presence of somatic mutations,8 while about 20–30% of CRC are associated with a family history,9,10 and 5–15% show hereditary diseases, including polyposis and nonpolyposis CRC (Fig 1). The common somatic mutations of CRC patients have been summarized in Table 1. There are several types of inherited CRC including hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), attenuated FAP, MUTYH-associated polyposis (MAP), hamartomatous polyps as the primary lesions in Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS), hyperplastic polyposis (HPP) and familial CRC (FCC) syndrome X.11 The etiologies of the remaining familial CRCs, which are more common compared with the well-characterized inherited syndromes, are not completely understood. However, common single nucleotide polymorphism (SNP) in genes that regulate metabolic pathways or affecting genes regulated by environmental or other genetic factors influence the incidence of this type of CRC.11

Full Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446063/