Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

Abstract

Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type-II but not in Type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance.

(Iso-)form Matters: Differential Implication of Vav3 Variants in Ovarian Cancer

“…The ability to selectively filter out platinum‐refractory patients by using Vav3.1 suggested a genuine role in drug resistance and once again emphasized the distinctly different biology of constitutively resistant ovarian cancers, which are typically insensitive to an entire class of chemotherapeutic drugs. It was therefore striking that we also found overexpression of Vav3.1 in stem‐like ovarian cancer subpopulation cells exhibiting a multi‐drug resistance phenotype conferred by ATP‐binding cassette drug transporters .…”

“…Although not proven, one possible explanation for the observed phenotype is that Vav3.1 has a regulatory function on the full‐length Vav3 alpha, potentially mediated through competition. Indeed, we found coexpression of both protein variants in primary ovarian cancer specimens, and remarkably, this was particularly obvious in platinum‐refractory samples . Furthermore, Vav3.1 is capable of efficient interaction with other proteins, as both Src homology 3 (SH3) and Src homology 2 (SH2) domains are preserved in the remaining molecule.…”

“…The interaction with other proteins is especially relevant, as isoforms of the same protein might compete for binding sites, potentially resulting in dominant-negative (or otherwise opposing) effects. Our recent results on the role of Vav3 in malignancy may represent one such example [1].…”

“…In a recent attempt to globally profile the stem‐like ovarian cancer side population , we employed microarray analysis to find that these cells strongly overexpress Vav3 . In a large cohort of patients with ovarian cancer, we found that Vav3 expression was substantially higher in tumor tissue compared with healthy ovarian epithelium.…”

Resistance to chemotherapy and anti-angiogenic therapy in ovarian cancer

“…In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing sensitized both taxane-and platinum-resistant tumours to chemotherapy [24]. Reimer et al demonstrated that truncated isoform Vav3.1 is highly expressed in OCSCs and clinically relevant in predicting prognosis and platinum-response as Vav3.1 may be decisively involved in mechanisms causing genuine multidrug resistance [25]. In contrast, in the environment-mediated drug resistance (EMDR) model, cancer cells interact with their surrounding microenvironment and enter a quiescent state due to the complex interplay between tumour and its microenvironment.…”