Investigations have revealed significant correlations between patient outcome and the expression levels of some of the angiogenesis regulating lncRNAs such as UBE2CP3, LINC00312, and HOTAIR [57,84,87]. In breast cancer, UBE2CP3 is highly expressed, promotes tumor angiogenesis, and is also associated with poor prognosis [18,87]. In patients with HCC, UBE2CP3 expression levels correlated with vessel density. Furthermore, patients overexpressing UBE2CP3 were found to exhibit a median overall survival (OS) that was lower than that of HCC patients with tumours that did not express UBE2CP3 [49]. Interestingly, the expression of UBE2CP3 is restricted to the tumour and has not been detected in the para-tumour tissue [49]. On the other hand, meta-analysis revealed that TUG1, SPRY4-1T1, and HULC did not correlate with lymph node metastasis in various cancers [49,51]. However, a correlation could be established between the expression levels of these three lncRNAs and low overall survival in cancer patients [50].

LncRNA associated with microvascular invasion in hepatocellular carcinoma (MVIH)​ was initially identified in hepatocellular carcinoma but was later also detected in other neoplasms such as breast cancer [84,85]. Its overexpression in HCC patients correlates with increased tumour vascularization and metastasis [51,85]. In a mouse model of HCC, the induced overexpression of MVIH stimulated angiogenesis and promoted tumour growth and metastasis [88]. Of note is that, in breast and non-small cell lung cancers, MVIH is associated with poor prognosis, while in HCC patients who undergo hepatectomy it is a predictor of low recurrence free survival [52,88,89,90]. UBE2CP3 and MVIH could thus be useful markers for monitoring patient response to cancer therapy [51,91,92]. HOX transcript anti-sense RNA (HOTAIR), the first antisense transcription lncRNA to be discovered, is overexpressed in cancer tissues compared to normal tissues. It is linked to the development of gastric cancer (GC), breast cancer, lung cancer, and liver cancer [51]. HOTAIR promotes the expression of Vascular endothelial growth factor (VEGF)​ and activates the PI3K/AKT/multidrug resistance protein 1 (MRP1) pathway through direct binding to miR-126. Data has shown that serum HOTAIR levels were higher in patients with oesophageal squamous carcinoma when compared to controls without cancer, and that HOTAIR levels correlate with tumour node metastasis (TNM) stage [93]. In gastric cancer, HOTAIR correlates with lymph node and distant metastasis, while in colorectal carcinomas it is associated with advanced stage and metastases [94]. H19, another angiogenesis-regulating lncRNA, is also associated with lymph node metastasis [51]. HOTAIR and H19 could serve as prognostic biomarkers in both gastric and colorectal carcinomas. Moreover, HOTAIR is currently used as a prognostic marker for recurrence in patients who have undergone liver transplantation [95]. Additionally, several studies have shown that blood levels of HOTAIR are good predictors of disease outcome [96,​97]. HOTAIR and PVT1 detected in the saliva were identified as possible biomarkers early pancreatic disease [98,99]. Another lncRNA, Homebox A11 antisense (HOXA11as) was highly expressed in cancerous tissue, and its expression showed a significant correlation with clinicopathological features in serous ovarian cancer (SOC) [100]. Additionally, patients with an elevated expression of HOXA11as had a significantly shorter progression-free and overall survival rates. These observations provide a basis for the further studies and the development of these lncRNAs as biomarkers.

Several lncRNAs that regulate tumor angiogenesis were shown to be aberrantly expressed in many cancers, making them an attractive target for drug design. Moreover, many of these lncRNAs are not readily detectable in normal tissue, and some are both tissue and cancer subtype specific [51,101]. A few studies have investigated the potential use of these lncRNAs as targets for cancer therapy mainly in preclinical models [65,67,102]. The silencing of SPRYT4-IT1, inhibits the migration of oesophageal squamous cell carcinoma cell in vitro, while NEAT1 suppression inhibits tumor cell growth through p53 [102]. In several independent studies, MALAT1 promoted angiogenesis in vitro and its silencing led to an increase in EC migration, while the inhibition of MALAT1 expression by GapmeR inhibited EC sprout formation [9,65,67]. HOTAIR expression levels were found to be high in cisplatin resistant ovarian cancer cells. The knockdown of HOTAIR in these cells led to the inhibition of tumor cell growth and invasiveness [103]. The silencing of HOTAIR by siRNAs inhibits tumour cell invasiveness in breast cancer and reduces tumor growth in pancreatic cancer [102]. Furthermore, the knockdown of HOTAIR has been shown to improve the sensitivity of tumour cells to cisplatin and doxorubicin. The silencing of CRNDE in colorectal cancer cells suppresses tumor cell growth and reduces resistance to chemotherapy [104]. While these studies have yielded positive results, they are in their infancy and much remains to be done. Additionally, recent reports on the mechanism of some lncRNAs reveal anecdotal results. The LINC000961 gene was shown to yield two molecules with different and opposing effects on angiogenesis [105]. Similarly, another angiogenesis-regulating lncRNA that has been explored for drug targeting is LincRNA-p21 [27]. While some studies showed that it correlates with microvessel density and that its silencing reduces VEGF expression, it was also found to be downregulated in tumour tissue [27]. These findings underscore the importance of more in-depth investigations to elucidate the roles and mechanisms of these lncRNAs.