Application of Oncolytic Viruses for Cure of Colorectal Cancer

Della Davis, S. S. Lahiri^*

Amity Institute of Biotechnology, Amity University, Noida, India

Abstract: Colorectal cancer is one of the most commonly diagnosed and lethal cancers worldwide. It is the resultant of multistep processes caused by the accumulation of genetic/epigenetic aberrations. The different therapeutic strategies like radiotherapy, chemotherapy and surgery, used individually or in different combinations, do not remove tumors or their progression all the time. Besides, these procedures involve surrounding cells and tissues. In case of surgery, which is possible only before metastasis, even a single cancer cell left out during surgery, cause further cancer. Focus has been laid in developing agents that could specifically target the cancer cells and leave out the remaining normal cells. This also attempt at total recovery. This was how the focus was laid on viral agents. Over the last two decades, due to various advancements in molecular biology, virotherapy has seen various developments. A special class of viruses called oncolytic viruses have been used as a therapeutic strategy against cancer. These agents have various inherent and engineered factors like enhanced tissue tropism, thereby providing high selectivity; armed with transgenes to deliver therapeutic genes and to perform tumor selective replication, all these factors proving them improved and evolved mechanisms, when compared with other cancer therapeutics. These oncolytic virus provide greater protection in association with herbal remedies. The purpose of this paper is to provide a detailed account of some of the current observations, developments and insights made in the field of oncolytic virotherapy for targeting colorectal cancer cells.  A panel of five oncolytic viruses i.e. adenovirus, herpes virus, reovirus, vaccinia virus and new castle disease virus that are under clinical studies for targeting colorectal cancer cells have been discussed.

Keywords: Oncolytic Virus; Colorectal Cancer, Oncolytic Virotherapy, Oncolysis, Targeted Therapy, Adenovirus, CRAds, Herpes Simplex Virus, Reovirus, Vaccinia Virus, New Castle Disease Virus, Immunostimulatory Response

Introduction

The colon is a tubular structure measuring approx. 1.5 m in length and varying diameters in an adult. The colon is continuous with the small intestine proximally at the ileocecal valve and ends distally at the anal verge. The rectum, 10 cm in length in the adult, begins at the peritoneal reflexion and follows the curve of the sacrum ending at the anal canal.

1.1.Colonic Crypt Organization

The colon is organized into four histologically distinct layers. The epithelial layer, at the luminal surface, consists of a single sheet of columnar epithelial cells folded into finger-like invaginations that are supported by the lamina propria to form the functional unit of the intestine, called crypts of Lieberkühn (Lc). There are four epithelial cell lineages. The terminally differentiated cells (enterocytes, goblet cells, and endocrine cells), which are found in the top third of the crypt, are derived from multipotent stem cells located at the bottom of the crypt. During asymmetric division, these multipotent cells undergo self-renewal and generate a population of transit amplifying cells that, upon migration upward through the crypt, proliferate and differentiate into one of the epithelial cell types of the intestinal wall. The fourth type of cells, the Paneth cells, differentiates during a downward migration to the base of the crypt, where they reside below the stem cell population¹.

A variety of functions have been attributed to Paneth cells. These functions include modulation of the intestinal microflora and maintenance of mucosal defense barriers

A normal human crypt contains roughly 2,000 cells and approx. 19 stem cells. Stem cells are defined by two functional properties: self-renewal and multipotency. Several molecules have been proposed as markers of stem cells in the intestine, including Musashi-1 (Msi-1), Hes1, integrins α2 and β1 subunits, EphB receptors, Bmi-1, Lgr5, and Aldh1.^{2, 3}

Source:Anatomy of the colon and retum, viewed on 8^th July, 2014 < http://www.hopkinsmedicine.org/gastroenterology_hepatology/diseases_conditions/small_large_intestine/>.

Fig. 1. (a) Anatomy of Colon (b) Anatomy of Rectum.

Source: Gastrointest Cancer Res. 2010 Nov-Dec; (Suppl 1): S16–S23.

Fig. 2. This represents the crypt of Lieberkühn, (a) Normal intestinal epithelium (b) Tumorigenic intestinal epithelium.

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