An Overview on Oncolytic Viruses as Cancer Therapy

The current regimen of cancer therapy (chemotherapy and radiotherapy) suffers from disadvantages such as a narrow therapeutic index that further facilitates tumor evolves drug resistance and severe side-effects. Oncolytic viruses are therapeutically useful anticancer viruses that will selectively infect and damage cancerous tissues without causing harm to the normal tissues.

Many naturally occurring Oncolytic viruses have a preferential tropism to the tumor or associated endothelial cells and others are genetically engineered to change their cellular or organ tropism toward cancer. Antitumor effect of Oncolytic viruses is either by locale cell death or by initiation of the systemic immune response against a tumor.

Oncolytic Adenovirus, Herpes Simplex Virus, Newcastle Disease Virus, and Reovirus are representative of Oncolytic viruses that have potential to lysis tumor. The effects of the host immune response on the efficacy of Oncolytic viruses are complex. But, using carrier cells as delivery vehicles could hide the viral antigen from antibodies and complements.

Oncolytic viruses have to be been combined with many cancer therapies to increase response to cancer. Since many forms of canine or feline neoplasmsresemble to a humane counterpart. So, oncologists believe that Oncolytic virotherapy could soon be a reality in veterinary medicine.

Oncolytic viruses

Oncolytic viruses are therapeutically useful anticancer viruses that will selectively infect and damage cancerous tissues without causing harm to the normal tissues. Each virus has a specific cellular tropism that determines which tissues are preferentially infected.

The field of Oncolytic virotherapy began as an observational science more than a century ago, when it was noted that cancer regressions sometimes occurred spontaneously in patients following certain viral infections.

Most people think of viruses as pathogenic microorganisms that infect cells, overtake their DNA, RNA and protein synthetic machinery to replicate and then lyse their host cell to spread their progeny, thereby propagating the infection throughout a tissue. Viral infection also results from cytopathic effects, such as induction of cell death and dysfunction.

With the advent of modern biotechnology tools and the better understanding of cancer biology and virology, it has become feasible to engineer viruses with increased tumor selectivity and enhanced oncolytic activity. Naturally occurring lytic viruses have evolved to infect, replicate and lyse cells. It is interesting that the replication cycle of many viruses exploits the cellular pathways that are altered in cancer cells.

The anticancer activities of OVs are derived from multimodal cancer-killing mechanisms. The first is the direct oncolysis of cancer cells by the virus. The second is the apoptotic and necrotic death of uninfected cells induced by anti-angiogenesis and antivasculature of the Oncolytic viruses as shown in animals and humans. The last is cytotoxicity to cancer and stromal cells by activated innate and tumor-specific immune cells.

Probably the most serious limitation to the successful application of Oncolytic virotherapy has been the limited ability to deliver viruses specifically and efficiently to the tumor, while perhaps its greatest strength has been the ability to achieve selective and efficient amplification of the virus and lysis of the cancer cells.

Through extensive investigations in the last few years, a number of novel strategies to achieve tumor-selective replication and potent oncolysis have been developed. In addition, the issue of tumor-selective systemic delivery of OVs via the use of carrier cellular vehicles has been explored.

Due to strong similarities between naturally occurring human and pet cancers, Oncolytic virotherapy has been used for canine or feline cancer patients.

Tumor Selectively Replication of Oncolytic Viruses

Cancer cells have several distinct hallmarks that separate them from normal cells: sustained growth signals, insensitivity to antigrowth signals, evasion of apoptosis, increased angiogenesis, cell immortality, and metastasis. OVs possess the ability to selectively infect and replicate in cancer and associated endothelial cells and kill these cells in cancerous tissues while leaving normal tissues unharmed. Many naturally occurring OVs have a preferential tropism for tumor and associated endothelial cells. Others are genetically engineered to change their cellular or organ tropism to cancer.

For instance, constitutively active PKB (Protein kinase B) pathway signaling serves as a sustained growth and survival signal in many different types of cancer. Wang and colleagues demonstrated that the natural tropism of myxoma virus in cancer cells capitalizes on endogenous PKB activity via complex formation between PKB and myxoma viral protein.

Cancer cells also have been shown to overexpress selected surface receptors, which is another mechanism by which viruses may selectively bind to and infect cancer cells. In squamous cell carcinoma, higher expression of the cell surface adhesion molecule nectin-1 correlated with increased HSV-1 infection and cytotoxicity compared to cells that had lower nectin-1 levels. Measles virus has been shown to utilize the surface receptor CD46 for cellular entry, which is overexpressed in a variety of human cancers, including hepatocellular carcinoma, colorectal cancer, ovarian cancer, and breast cancer.

In addition, OVs can also capitalize on deficient anti-viral defense mechanisms in cancer cells. When normal cells are infected by viruses, a release of IFNs and activation of TLRs (Toll-like Receptors) by recognition of viral elements activate several downstream pathways, leading to protein kinase R (PKR) activation. Phosphorylated PKR subsequently blocks protein synthesis and prevents viral replication in the cell. Cancer cells have abnormal IFN pathways and abnormal PKR activity, making them more susceptible to viral infection.

Also, viral gene inactivation is a commonly used strategy to limit viral infection in cancer cells which often capitalizing the alterations in cellular metabolism and survival pathways of transformed cells. For example, Adenovirus can be used as an Oncolytic virus after genetic modification; the modified version replicates and proliferates only in cancer cells with an abnormal p53 (Tumor suppressor protein 53) mediated cell cycle.

The adenovirus E1B gene has been found to inactivate the tumor suppressor protein p53, so that adenovirus with a deleted E1 gene has a relatively high replication rate in cancer cells with deficient p53 because it no longer expresses E1B protein.

Transcriptional targeting is another method that is used to produce tissue-specific OVs replication by putting viral essential genes under the control of desirable promoters. The adenovirus can design with the E1A viral protein (essential for viral replication) under control of the prostate-specific antigen promoter.

Since prostate cancer cells express higher levels of PSA more highly than normal cells, E1A is selectively expressed in these cells, resulting in viral replication and eventual oncolysis. However, normal cells, which do not express PSA at high levels, will not generate significant amounts of E1A, resulting in defective viral replication and, thus, careful healthy tissue from lysis.

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This article first published in International Journal of Cancer Studies & Research  by scidoc 
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