Truncated Isoform Vav3.1 is Highly Expressed in Ovarian Cancer Stem Cells

Ovarian cancer is considered to be the most lethal gynecologic cancer in western countries. Scientists discovered before that GTP-hydrolases from the Rho/Rha family proteins are involved in the oncogenic events associated with ovarian cancer. These proteins may either trigger the metastatic potential of transformed cells or act as factors that contribute to the transforming activity of oncoproteins. Rho/Rha activity is regulated by GTPase activating proteins (GAPs), guanine nucleotide dissociation inhibitors (GDIs) and guanine nucleotide exchange factors (GEFs). The best characterized proteins within the group of GEFs are the Vav family proteins that play a major role in signal transduction and act as Rho/Rac protein modulators.

Vav3 proteins are major modulators of GTP-hydrolases, which play a pivotal role in cell proliferation. The major isoforms produced from the alternative splicing of Vav3 include full-length Vav3-alpha and N-terminal truncated Vav3.1 (which lack self-regulatory domains). Although previous studies have suggested that Vav3 proteins are involved in tumorigenesis, angiogenic response within the tumor microenvironment and prognosis in different tumors, the exact role of the truncated Vav3.1 isoform has remained unknown.

Hence, Dr. Daniel Reimer at Medical University Innsbruck in Austria and his colleagues demonstrated for the first time the role of distinct Vav isoforms in ovarian cancer. The research work is published in the International Journal of Cancer.

The authors observed an increase in Vav3.1 protein abundance compared to the minor elevation of Vav3-alpha protein expression in the SP fractions of ovarian cancer cell lines. They also observed a significant overexpression of Vav3-alpha and Vav3.1 in the tumor specimens. Contrastingly, Vav1 expression was not detected while low levels of Vav2 expression were detected. The expression of Vav3.1 was found to be significantly increased with higher FIGO stage and residual disease.

In addition, the research team discovered that Vav3.1 was an independent prognostic variable that predicted progression-free survival and overall survival in the whole study cohort as well as in the Type-II cancers. However, only the age at diagnosis and residual disease retained independent prognostic significance for both survival measures.

Although Vav2 and Vav3-alpha expression in cancers was independently distributed with regard to the degree of platinum responsiveness, Vav3.1 was expressed at significantly higher levels in platinum-refractory cancers compared to all other cancers.

This novel study by Daniel Reimer and colleagues provides compelling evidence that the N-terminal truncated Vav3.1 isoform is clinically relevant in the pathophysiology of ovarian cancer. These findings will stimulate further studies on the exact mechanism underlying genuine drug resistance in ovarian cancer and the potential use of N-terminal truncated Vav3.1 as an early biomarker to predict the prognosis and clinical response of patients to platinum-based chemotherapy.