A recent study has uncovered that a group of glycoproteins, called laminins, are essential for fighting and killing cancer cells, meaning that oncolytic viruses move closer to becoming effective anticancer therapies.
Oncolytic viruses are a group of viral infections that act in several ways to kill cancer cells. They do this by selectively targeting and replicating in the cancer cells, whilst leaving healthy cells and tissues unharmed. Oncolytic viruses are also capable of engaging the immune system to reshape the tumour environment. Moreover, they can disrupt the tumour vasculature to induce the death of cancer cells via the deprivation of oxygen and nutrients.
The H-1 parvovirus (H-1PV) is an oncolytic virus that is naturally hosted by rats. In the 1950’s, it was discovered that infection by H-1PV could supress viral- and chemically-induced tumours. Since then, the idea that H-1PV could be used therapeutically in human cells has become more established. Now, H-1PV is considered as a promising anticancer therapy. Nevertheless, an in-depth understanding of the virus’s life cycle, including the host cell factors that it requires for infectivity, is lacking.
Consequently, the use of H-1PV as a standalone treatment does not currently result in complete tumour regression. Therefore, the knowledge of which genetic characteristics of tumours cause vulnerability to H-1PV is crucial for understanding the varying degrees of patient sensitivity and responsiveness to oncolytic anticancer therapy.
Laminins γ1 and β1
Researchers at the Luxembourg Institute of Health (LIH) have recently focussed on the development of novel anticancer strategies based on oncolytic viruses. To investigate which host cell factors are involved in H-1PV infectivity, siRNA library screening was carried out using a druggable genome library. siRNA screening is a powerful approach used to study the structural and functional relationships of genes and is extensively used for the validation of drug targets.
The team identified 151 genes that served as activators, and 89 genes that were repressors, for the cancer-killing action of H-1PV. A group of glycoproteins, called laminins, were found to be critical modulators for H-1PV infection. Laminins carry out essential roles in the organisation of the basement membranes, which provide cells with support and act as a platform for complex signalling. Laminin proteins are made up of several chains, the most abundant being laminin γ1, encoded for by LAMC1. Laminin γ1 was found to be fundamental in the attachment and penetration of tumour cells by H-1PV.
Additionally, deactivating the LAMC1 gene in several different types of cancer resulted in a significant increase of cancer cell resistance to virus-induced death. A similar effect was also observed when switching off the LAMB1 gene, which encodes the laminin β1 chain. The researchers found that this effect was due to the differential expression of γ1 and β1 laminins in different tumours.
Laminins in anticancer strategies
These findings have significant implications for the advancement of oncolytic anticancer strategies. The results have provided insights that may help the development of more effect viruses for treatments and guide the identification of biomarkers for the susceptibility to H-1PV treatment.
Dr Marchini, one of the researchers, said: “These observations indicate that elevated laminin expression is associated with poor patient prognosis and survival in a variety of tumours, including gliomas and glioblastoma. The encouraging fact, however, is that cancers displaying high laminin levels are more susceptible to being infected and destroyed by the H-1PV virus and that patients with these tumours are therefore more likely to be responsive to this therapy”.
In the future, cancer patients could be classified according to their individual laminin expression levels, which could enhance the ability to predict a patient’s response to H-1PV strategies. For example, tumours with elevated levels of γ1 and β1 laminins may be more susceptible to virus-based anticancer treatments. Subsequently, this will not only create more efficient and less costly clinical trials, but also considerably improve patient outcomes.
Image credit: FreePik miss.lemon