Could HHV-6 U94 attenuate tumor cell growth and metastasis?

In past work, HHV-6 has been suggested as a possible trigger or co-factor in several malignancies. The results from a new study reveal that the HHV-6 latency-associated gene U94, inserted in a HSV-1 vector, can inhibit development of breast cancer, cervical cancer, and lung metastasis in vivo as well as impair tumor driven angiogenesis. The authors hope this finding may open the door to research on a new broad spectrum cancer therapy for tumors and metastasis.

Study authors, L to R, Pietro Mazzuca, Federica Campilongo, Prof Arnaldo Caruso, Francesca Caccuri and Roberto Ronca.

U94 has previously been found to inhibit angiogenesis and lymphangiogenesis (Caruso 2009). To delve deeper into this finding, Caccuri et al. began by testing the effects of HHV-6B U94 on a breast cancer cell line. Inhibition of the proto-oncogene pSrc was confirmed as a result of expression of U94. The infected cells exhibited less migration, reduced invasiveness through the extracellular matrix, and a partial mesenchymal-to-epithelial transition (MET) in vitro. The MET was characterized in part by disappearance of atypias (structurally abnormal cells) and increased cell-cell adhesion, β-catenin primarily localized in the membrane instead of the cytoplasm, and lower vimentin expression. Cumulatively, the results depicted a switch from an aggressive to a more differentiated tumor phenotype.

Next, the investigators injected the U94 transfected cells into mice and examined the tumors after 23 days. Compared to controls, U94+ mice developed smaller, well-defined tumors without the extensive vasculature present in the tumors of U94- mice. Similarly, U94 expression was associated with less lung metastasis in vivo. U94-expressing cervical cancer cells also triggered Src down-modulation and resulted in significantly reduced tumor growth.

In 2014, the HHV-6B U54 gene was also shown to inhibit breast cancer cell proliferation in vitro (Iampietro 2014). On the other hand, iciHHV-6 U94 was recently identified as a possible player in the appearance of marker chromosomes involved in lymphoma (Campioni  2017). Continued research on this unique gene is warranted.

Read the full paper here: Caccuri 2017.