Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma

Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

Research Progress of Anti-Tumor Angiogenesis in Traditional Chinese Medicine

In recent years, seeking effective anti-angiogenic components and therapeutic methods from traditional Chinese Medicine (TCM) has been a hot spot in the treatment of malignant tumors. In particular, the active ingredients found in Chinese herbal extracts have shown strong inhibition of tumor neovascularization.

Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma

Primary pulmonary nuclear protein of testis carcinoma is a rare and highly aggressive malignant tumor. It accounts for approximately 0.22% of primary thoracic tumors and is little known, so it is often misdiagnosed as pulmonary squamous cell carcinoma. No effective treatment has been formed yet, and the prognosis is extremely poor. This review aims to summarize the etiology, pathogenesis, diagnosis, treatment, and prognosis of primary pulmonary nuclear protein of testis carcinoma in order to better recognize it and discuss the current and innovative strategies to overcome it. With the increasing importance of cancer immunotherapy and tumor microenvironment, the review also discusses whether immunotherapy and targeting the tumor microenvironment can improve the prognosis of primary pulmonary nuclear protein of testis carcinoma and possible treatment strategies. We reviewed and summarized the clinicopathological features of all patients with primary pulmonary nuclear protein of testis carcinoma who received immunotherapy, including initial misdiagnosis, disease stage, immunohistochemical markers related to tumor neovascularization, and biomarkers related to immunotherapy, such as PD-L1 (programmed death-ligand 1) and TMB (tumor mutational burden). In the meanwhile, we summarized and analyzed the progression-free survival (PFS) and the overall survival (OS) of patients with primary pulmonary nuclear protein of testis carcinoma treated with PD-1 (programmed cell death protein 1)/PD-L1 inhibitors and explored potential population that may benefit from immunotherapy. To the best of our knowledge, this is the first review on the exploration of the tumor microenvironment and immunotherapy effectiveness in primary pulmonary nuclear protein of testis carcinoma.

Vasculogenic Mimicry in Breast Cancer: Clinical Relevance and Drivers

In solid tumors, vasculogenic mimicry (VM) is the formation of vascular structures by cancer cells, allowing to generate a channel-network able to transport blood and tumor cells. While angiogenesis is undertaken by endothelial cells, VM is assumed by cancer cells. Besides the participation of VM in tumor neovascularization, the clinical relevance of this process resides in its ability to favor metastasis and to drive resistance to antiangiogenic therapy. VM occurs in many tumor types, including breast cancer, where it has been associated with a more malignant phenotype, such as triple-negative and HER2-positive tumors. The latter may be explained by known drivers of VM, like hypoxia, TGFB, TWIST1, EPHA2, VEGF, matrix metalloproteinases, and other tumor microenvironment-derived factors, which altogether induce the transformation of tumor cells to a mesenchymal phenotype with a high expression rate of stemness markers. This review analyzes the current literature in the field, including the participation of some microRNAs and long noncoding RNAs in VM-regulation and tumorigenesis of breast cancer. Considering the clinical relevance of VM and its association with the tumor phenotype and clinicopathological parameters, further studies are granted to target VM in the clinic.

Arterial instillation of rapamycin in treatment of rabbit hepatic xenograft tumors and its effects on VEGF, iNOS, HIF-1α, Bcl-2, Bax expression and microvessel density

Hepatocellular carcinoma is one of the leading causes of malignant tumor related death word wide with poor prognosis. Chemotherapy and TACE are main treatment methods for advanced stage cases. Rapamycin, a macrolide compound that initially used to coat coronary stents, can inhibit the growth of a variety of cancer cells especially hepatocellular carcinoma. Twenty-four healthy adult New Zealand white rabbits underwent CT-guided puncture to prepare a model of VX2 liver xenograft tumor. The rabbits were randomly divided into four groups with six in each group and received the following treatments: APR-TACE1: arterial perfusion of high-dose rapamycin combined with TACE; APR-TACE2: arterial perfusion of low-dose rapamycin combined with TACE; TACE: TACE alone; and IVR-TACE: intravenous injection of rapamycin combined with TACE. Two weeks after TACE treatment, the rabbits received CT scan and DSA angiography examination, and then killed by air embolism. The non-necrotic region and surrounding tissues were obtained from the peripheral tumor for iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression analysis. Protein expression of iNOS, HIF-1α, VEGF, and Bcl-2 in APR-TACE1 were significantly lower than those in groups APR-TACE2, TACE, and IVR-TACE ( p < 0.05). iNOS, HIF-1α, and VEGF in APR-TACE2 were lower than those in TACE ( p < 0.05). iNOS and VEGF in APR-TACE2 were significantly lower than those in IVR-TACE ( p < 0.05). iNOS in IVR-TACE was significantly lower than that in TACE ( p < 0.05). The expression levels of Bcl-2 and Bax were statistically significant between APR-TACE2 and TACE ( p < 0.05). The MVD of the tumor tissue in APR-TACE1 was lower than that of groups APR-TACE2, TACE, IVR-TACE with statistical difference ( p < 0.05). However, MVD of APR-TACE2 was lower than that of groups TACE, IVR-TACE with significant statistical difference ( p < 0.05). Arterial instillation of rapamycin+TACE in treatment of rabbit hepatic xenograft tumors can reduce tumor neovascularization and inhibit iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression.

The nanomedicine system has successfully inhibited tumor neovascularization using gene silencing, chemotherapy, photothermal therapy, and other therapies

Customized nanomedicines can be used in a variety of ways, including angiogenesis suppression, vascular disruption, and vascular infarction. In the angiogenesis suppression approach, VEGF, VEGFR, mTOR, EGFR, bFGF, ROS, and other components have become promising therapeutic targets. The nanomedicine system has successfully inhibited tumor neovascularization using gene silencing, chemotherapy, photothermal therapy, and other therapies. In the vascular disruption approach, VDAs supplied by nanomaterials were bonded with the bonding sites of CA4, COL, PTX, and other medications on microtubules to promote rapid disintegration of tumor vascular wall cells. Combining many medicines increased the tumor treatment outcome even more. For example, disruption of tumor blood arteries caused by nanoparticle-mediated physical methods combined with chemotherapy resulted in effective treatment in a large volume tumor model. The vascular infarction methodology uses a variety of carriers, including nanoparticles, DNA nanorobots, platelet membranes, and others, to carry thrombin, tTF, and other drugs to generate local thrombosis and provide safe and effective tumor treatment.

Cancer Stem Cells and Neovascularization

Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization.

The Correlation between Targeted Contrast-Enhanced Ultrasound Imaging and Tumor Neovascularization of Ovarian Cancer Xenografts in Nude Mice

In order to explore the correlation between targeted contrast-enhanced ultrasound imaging and tumor neovascularization of ovarian cancer xenografts in nude mice, a total of 49 nude mice were selected and randomly divided into 1-week group, 2-week group, 3-week group, 4-week group, 5-week group, 6-week group, and 7-week group according to their ovarian cancer xenografts’ growth time, with 7 ovarian cancer xenografts in each group. After preparing antibody-carrying targeted contrast agent, each group of xenografts performed normal and targeted contrast ultrasound examinations to obtain peak intensity, time to peak, and other imaging parameters; then, those ovarian cancer xenografts were sacrificed for pathological analysis: the neovascular density and antibody expression of the cancer xenografts at different stages were observed and counted, and the correlation between targeted contrast-enhanced ultrasound parameters and tumor neovascular densities of the ovarian cancer xenografts was analyzed. The results show that the peak intensities of targeted contrast ultrasound imaging are greater than that of ordinary ultrasound imaging in the 2-, 3-, 4-, and 5-week groups with statistically significant differences ( P < 0.05 ); the time to peak of targeted contrast ultrasound imaging is shorter than that of ordinary ultrasound imaging in the 2-, 3-, 4-, and 5-week groups with statistically significant differences ( P < 0.05 ); there is a positive correlation between the peak intensities of targeted contrast ultrasound imaging and tumor neovascular densities of the ovarian cancer xenografts in the 2-, 3-, and 4-week group (r2 = 0.645, r3 = 0.668, and r4 = 0.693, P < 0.05 ); there is a negative correlation between the time to peak of targeted contrast ultrasound imaging and tumor neovascular densities of the ovarian cancer xenografts in the 2-, 3-, and 4-week groups (r2 = −0.669, r3 = −0.692, and r4 = −0.704, P < 0.05 ). Therefore, the targeted contrast-enhanced ultrasound imaging parameters have a certain correlation with tumor neovascular density of ovarian cancer xenografts in nude mice and this correlation is more significant in the early stage of ovarian cancer; hence, targeted contrast-enhanced ultrasound imaging may provide a new method, new idea, and new basis for the diagnosis of early ovarian cancer.