As an endogenous inhibitor of angiogenesis, VASH1 may play a pivotal role in maintaining vascular homeostasis, preventing pathological angiogenesis . VASH1 may possess the duality functions - an experiment based on the mice model stated that the decrease of VASH1 resulted in a long lifespan, which contrary to the prime expectation of the experimenters . Meanwhile, the feasible suppression and facilitation of VASH1 on tumors have of late years investigated by scholars and the results remain controversial [37, 38].
Meta-analysis can provide more reliable results compared with a single study and serves as a powerful tool to explain controversial conclusions. For this reason, we performed a meta-analysis to clarify whether VASH1 expression has a significant impact on the clinical and prognostic outcomes of cancer. To our knowledge, this is the first complete meta-analysis concerning the role of VASH1 in solid tumors. In our analysis, we found that VASH expression was relevant to more aggressive clinicopathological parameters and might predict inferior DFS and OS in cancer patients.
The result of our analysis showed that high expression of VASH1 might be associated with more inferior TNM stage, tumor stage, lymph node metastasis, distant metastasis and tumor grade, same as the conclusion with many studies, for example, Cao et al. and Zhang et al. [39, 40]. Despite the concrete mechanism not being clearly understood, an accountable explanation is that - in the process of tumor angiogenesis, the out-off-balance between VASH1 and VEGF may lead to the formation of numerous new blood vessels with fragmentary structure or lack of basement membrane, although the inhibition role of VASH1 in tumor vascularization. And the noteworthy increase of vascular permeability caused by this imbalance could further accelerate the proliferation and metastasis of cancer cells . Put another way, VASH1 suppresses tumor angiogenesis but not the tumor cells.
MVD, as an independent predictor of poor prognosis, is generally regarded connected with clinical outcome, for instance, tumor grade, pathologic stage et al. [42, 43]. Additionally, from the present analysis, an advanced relevance between venous invasion, MVD, and VASH1 expression was found, which was opposite to our expectations. Interestingly, considering that the indispensable effect of VASH1 on maintaining vascular health and inhibiting angiogenesis, this unexpected result is worth a thorough discussion. Firstly, as we know, VASH1 is induced by angiogenic factors, to illustrate, VEGF and FGF-2 . There is a positive relevance between the intensity of VASH1 and VEGFA in tumor cells [31, 44]. Nevertheless, with VASH1 degraded and inactivated after its secretion in the tumor microenvironment, the IHC staining of VASH1 in vascular ECs may not demonstrate its anti-angiogenic activity, but only reflect the response of ECs to angiogenic stimulation . Secondly, as a feedback regulator of angiogenesis, VASH1 is up-regulated with VEGFA expression. Yet this endogenous up-regulation is not enough to inhibit neovascularization. Researchers found that in tumor tissue, not only MVD expression increased but also the more ripe microvasculature where the VASH1 mainly expressed . These mature vasculature may supply more nutrition for tumors, and therefore facilitate tumor growth and distant metastasis. Consequently, the increase of VASH1 expression may be associated with the enhancement of tumor invasiveness [25, 27]. Thirdly, VASH1 might be an activator or inhibitor of angiogenic factor mRNA translation, and this dual functional role may be the reason for VASH1 to inhibit angiogenesis and to profit ECs survival [47, 48].
Finally, our results showed that the higher expression of VASH1 associated with shorter DFS and OS time, which was in line with conclusions from most studies [33, 34]. From our perspective, the high expression of VASH1 is related to worse clinicopathological features and thus shorten survival time. However, the results of the OS time showed high heterogeneity, which might be caused by different types of solid tumors.
Furthermore, despite the overall robust statistical evidence generated through this analysis, some limitations have been identified. Firstly, owing to the limited quantity of the studies included, further subgroup analysis is unavailable, for example, cancer types. Secondly, IHC based VASH1 detection has limitations for its subjectivity in determining a clear definition of "positive (or high)" tumor VASH1 staining. Meanwhile, different studies had different definitions of positive expression of VASH1 (final scores, VASH1 density, IHC expression level, et al. ), and thus more uniform standards need to be established. Thirdly, only the Asian population was applicable in this meta-analysis, which might minimize the analyzing value to some level. Moreover, the difference in samples from different institutions might reduce the credibility of our conclusion, which serves as an unavoidable factor in the study.