The Correlation between VEGF and CD34 Protein Marker and Pyogenic Granuloma.

BACKGROUND: A typical non-neoplastic connective tissue proliferations called a pyogenic granuloma. A vascular adhesion molecule used to assess angiogenesis is the CD34 marker. The primary memberof a family of growth factors, VEGF helps in generating and maintaining the lymphatic and blood circulation systems. OBJECTIVE: The aim of the study was to know the correlation between VEGF and CD34 protein marker and pyogenic granuloma. METHODS: Thirty-one formalin fixed paraffin embedded (FFPE) blocks were taken from female pyogenic granuloma patients ranging in age from 29 to 70. The IHC was used to identify VEGF and CD34 expression in the cytoplasm of the cells. RESULTS: Seventeenout of 31 patients had VEGF positive expression. Twenty-sixout of 31 had CD34 positive expression and 5 with no expression (negative expression). Brown-stained cytoplasm showed high VEGF and CD34 expression, whereas blue stained cytoplasm showed no VEGF and CD34 expression in these cells. CONCLUSIONS: The results suggest the role of suchbiomarkers in the oral pyogenic granuloma pathogenesis, and it appears that CD34 and VEGF are valuable biomarkers in evaluating vascular and inflammatory diseases like pyogenic granuloma.

ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

AZGP1 deficiency promotes angiogenesis in prostate cancer.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer.

BACKGROUND: Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear. METHODS: Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression. RESULTS: Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis. CONCLUSION: The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.

BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma.

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.

Effects of aflibercept and bevacizumab on cell viability, cell metabolism and inflammation in hypoxic human Müller cells.

Anti-VEGF (vascular endothelial growth factor) drugs such as aflibercept (AFL) and bevacizumab (BVZ) inhibit pathological neo-angiogenesis and vascular permeability in retinal vascular diseases. As cytokines and growth factors are produced by Müller glial cells under stressful and pathological conditions, we evaluated the in vitro effect of AFL (Eylea®, 0.5 mg/mL) and BVZ (Avastin®, 0.5 mg/mL) on cell viability/metabolism, and cytokine/growth factor production by Müller cells (MIO-M1) under cobalt chloride (CoCl2)-induced hypoxia after 24h, 48h and 72h. Cell viability/metabolism were analyzed by Trypan Blue and MTT assays and cytokine/growth factors in supernatants by Luminex xMAP-based multiplex bead-based immunoassay. Cell viability increased with AFL at 48h and 72h and decreased with BVZ or hypoxia at 24h. BVZ-treated cells showed lower cell viability than AFL at all exposure times. Cell metabolism increased with AFL but decreased with BVZ (72h) and hypoxia (48h and72h). As expected, AFL and BVZ decreased VEGF levels. AFL increased PDGF-BB, IL-6 and TNF-α (24h) and BVZ increased PDGF-BB (72h). Hypoxia reduced IL-1ß, -6, -8, TNF-α and PDGF-BB at 24h, and its suppressive effect was more prominent than AFL (EGF, PDGF-BB, IL-1ß, IL-6, IL-8, and TNF-α) and BVZ (PDGF-BB and IL-6) effects. Hypoxia increased bFGF levels at 48h and 72h, even when combined with anti-VEGFs. However, the stimulatory effect of BVZ predominated over hypoxia for IL-8 and TNF-α (24h), as well as for IL-1ß (72h). Thus, AFL and BVZ exhibit distinct exposure times effects on MIO-M1 cells viability, metabolism, and cytokines/growth factors. Hypoxia and BVZ decreased MIO-M1 cell viability/metabolism, whereas AFL likely induced gliosis. Hypoxia resulted in immunosuppression, and BVZ stimulated inflammation in hypoxic MIO-M1 cells. These findings highlight the complexity of the cellular response as well as the interplay between anti-VEGF treatments and the hypoxic microenvironment.

A Molecular Perspective on HIF-1α and Angiogenic Stimulator Networks and Their Role in Solid Tumors: An Update.

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors' progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

Group XIV C-type lectins: emerging targets in tumor angiogenesis.

C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each's role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.

Dynamic contrast-enhanced magnetic resonance imaging assessment of residual tumor angiogenesis after insufficient microwave ablation and donafenib adjuvant therapy.

To analyze the correlation between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) permeability parameters and serum vascular endothelial growth factor (VEGF) levels in a rabbit VX2 liver cancer model with insufficient microwave ablation (MWA), to observe the dynamic changes in residual tumor angiogenesis in the short term after MWA, and to assess the effectiveness of donafenib as adjuvant therapy. Forty rabbits with VX2 liver tumors were randomly divided into three groups: an insufficient MWA group (n = 15), a combined treatment group (n = 15) and a control group (n = 10). The dynamic changes in VEGF expression after MWA and the effectiveness of donafenib as adjuvant therapy were evaluated by DCE-MRI and serum VEGF levels before surgery and 1, 3, 7, and 14 days after surgery. The correlation between the volume translate constant (Ktrans) of DCE-MRI parameters and serum VEGF levels fluctuated after ablation, but the coefficient was always positive (all p < 0.001). Repeated-measures ANOVA revealed significant changes in the serum VEGF concentration (F = 40.905, p < 0.001; partial η2 = 0.689), Ktrans (F = 13.388, p < 0.001; partial η2 = 0.420), and tumor diameter in each group (F = 34.065, p < 0.001; partial η2 = 0.648) at all five time points. Pairwise comparisons showed that the serum VEGF level, Ktrans value and tumor diameter in the insufficient MWA group and combined treatment group were significantly lower at 1 d than in the control group, but these values gradually increased over time (all p < 0.05). Ktrans and tumor diameter were significantly greater in the insufficient MWA group than in the control group at 14 days (all p < 0.05). The serum VEGF concentration, Ktrans, and tumor diameter were significantly lower in the combined treatment group than in the other two groups at 3, 7, and 14 days (all p < 0.05). Ktrans is positively correlated with the serum VEGF concentration. Ktrans and the serum VEGF concentration changed significantly after treatment with insufficient ablation or in combination with donafenib, and Ktrans may change faster. Insufficient MWA promotes the progression of residual tumors. Adjuvant treatment with donafenib is effective.

Small extracellular vesicles promote the formation of the pre-metastatic niche through multiple mechanisms in colorectal cancer.

Colorectal cancer (CRC) ranks among the most prevalent global malignancies, posing significant threats to human life and health due to its high recurrence and metastatic potential. Small extracellular vesicles (sEVs) released by CRC play a pivotal role in the formation of the pre-metastatic niche (PMN) through various mechanisms, preparing the groundwork for accelerated metastatic invasion. This review systematically describes how sEVs promote CRC metastasis by upregulating inflammatory factors, promoting immunosuppression, enhancing angiogenesis and vascular permeability, promoting lymphangiogenesis and lymphatic network remodeling, determining organophilicity, promoting stromal cell activation and remodeling and inducing the epithelial-to-mesenchymal transition (EMT). Furthermore, we explore potential mechanisms by which sEVs contribute to PMN formation in CRC and propose novel insights for CRC diagnosis, treatment, and prognosis.

Exploring the therapeutic potential of curcumin in oral squamous cell carcinoma (HSC-3 cells): Molecular insights into hypoxia-mediated angiogenesis.

BACKGROUND: Oral cancer represents a substantial global health burden, often associate with hypoxia-induced angiogenesis as a critical factor in its progression. Curcumin, a naturally occurring bioactive compounds, has gained increasing attention for its potential anticancer properties. OBJECTIVE: To assess the impact of curcumin on oral cancer, particularly its role in modulating HIF-1α-mediated angiogenesis in HSC-3 cells. METHODS: Our investigation involved multiple experimental approaches, including MTT assay, aerobic glycolysis by metabolic kit, cell cycle, and apoptosis assessment via flow cytometry. Furthermore, we employed molecular docking techniques to examine the interactions between curcumin and key angiogenesis related proteins, including HIF-1α, VEGF-B, MMP-3, and STAT3. RESULTS: Our results demonstrate that curcumin exerts significant effects on the cell survivability, cell cycle regulation, and apoptosis induction in oral cancer cells. These effects were particularly pronounced under the conditions of HIF-1α mediated angiogenesis. Computational binding analysis revealed strong binding interactions with curcumin and the selected proteins, implying a plausible mechanism through which curcumin may modulate the angiogenic pathways in oral cancer. CONCLUSION: Our research sheds light on the diverse effects of curcumin on oral cancer cells, emphasizing its potential as a promising therapeutic tool for addressing hypoxia-induced angiogenesis. However, further investigation is essential to comprehensively understand the molecular mechanisms underlying these effects in in vitro models. This deeper comprehension is crucial for translating these findings into clinical applications aimed at improving oral cancer treatment.

Endosialin in Cancer: Expression Patterns, Mechanistic Insights, and Therapeutic Approaches.

Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly expressed in the stroma, especially in cancer-associated fibroblasts and pericytes, in most solid tumors. Endosialin is also expressed in tumor cells of most sarcomas. Endosialin can promote tumor progression through different mechanisms, such as promoting tumor cell proliferation, adhesion and migration, stimulating tumor angiogenesis, and inducing an immunosuppressive tumor microenvironment. Thus, it is considered an ideal target for cancer treatment. Several endosialin-targeted antibodies and therapeutic strategies have been developed and have shown preliminary antitumor effects. Here, we reviewed the endosialin expression pattern in different cancer types, discussed the mechanisms by which endosialin promotes tumor progression, and summarized current therapeutic strategies targeting endosialin.

Vascularized tumor-on-chip microplatforms for the studies of neovasculature as hope for more effective cancer treatments.

Angiogenesis is the development of new blood vessels from pre-existing vasculature. Multiple factors control its course. Disorders of the distribution of angiogenic agents are responsible for development of solid tumors and its metastases. Understanding of the molecular interactions regulating pathological angiogenesis will allow for development of more effective, even personalized treatment. A simulation of angiogenesis under microflow conditions is a promising alternative to previous studies conducted on animals and on 2D cell cultures. In this review, we summarize what has been discovered so far in the field of vascularized tumor-on-a-chip platforms. For this purpose, we describe different vascularization techniques used in microfluidics, present various attempts to induce angiogenesis-on-a-chip and report some approaches to recapitulate vascularized tumor microenvironment under microflow conditions.

Neovascularization of native cardiac valves, and correlation with histopathologic, clinical, and radiologic features.

Native cardiac valves in the setting of chronic injury undergo remodeling that includes fibrous thickening and dystrophic calcification, as well as neovascularization, that result in abnormal valve function. In order to characterize the presence of neovascularization in valves, a retrospective review of 1246 sequentially reviewed native cardiac valves of all types was performed, with correlation with other histopathologic features, and clinical and echocardiographic findings. Neovascularization was present in 55.5% of cases, with the greatest prevalence amongst aortic valves. While microvasculature (representing capillaries, venules, and/or lymphatics) was at least present in all cases of valves with neovascularization, arterial vessels were never identified in valves without also the finding of concomitant microvasculature present. Patients with neovascularization had a greater mean age and body mass index compared to those without, and the proportions of cases with significant coronary artery disease, dyslipidemia, diabetes mellitus, rheumatic fever, and malignancy were greater in the setting of valves with neovascularization compared to cases without. The rate of neovascularization increased with degree of valve thickening and/or calcification, and stenosis; in contrast, neovascularization was observed at a greater rate with decreasing degrees of regurgitation. The prevalence rates of hemosiderin-laden macrophages, osseous metaplasia, chondromatous metaplasia, smooth muscle, and chronic inflammation were greater in valves with neovascularization compared to valves without. Neovascularization within native cardiac valves is a frequent histopathologic alteration associated with chronic valve disease, likely representing a constituent of structural remodeling that mediates and reflects chronic injury.

Anti-angiogenesis in colorectal cancer therapy.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.

The N6-methyladenosine modification in pathologic angiogenesis.

The vascular system is a vital circulatory network in the human body that plays a critical role in almost all physiological processes. The production of blood vessels in the body is a significant area of interest for researchers seeking to improve their understanding of vascular function and maintain normal vascular operation. However, an excessive or insufficient vascular regeneration process may lead to the development of various ailments such as cancer, eye diseases, and ischemic diseases. Recent preclinical and clinical studies have revealed new molecular targets and principles that may enhance the therapeutic effect of anti-angiogenic strategies. A thorough comprehension of the mechanism responsible for the abnormal vascular growth in disease processes can enable researchers to better target and effectively suppress or treat the disease. N6-methyladenosine (m6A), a common RNA methylation modification method, has emerged as a crucial regulator of various diseases by modulating vascular development. In this review, we will cover how m6A regulates various vascular-related diseases, such as cancer, ocular diseases, neurological diseases, ischemic diseases, emphasizing the mechanism of m6A methylation regulators on angiogenesis during pathological process.

Expression patterns and pathogenesis of Semaphorin class 4 subfamily proteins in solid tumors.

Semaphorins are originally described as regulators of nervous system development. Besides, members of the semaphorin family play important roles in the growth, metastasis, and angiogenesis of solid tumors. In contrast to the other semaphorin subclasses, semaphorin class 4 has both membrane-bound and active soluble forms. Soluble class 4 semaphorins in body fluids (blood and saliva) may serve as potential biomarkers for early diagnosis and prognosis prediction of specific cancers. The class 4 semaphorins also transduce signal in cancer cells in a cell membrane-bound form, thereby regulating cancer progression. In solid tumors, class 4 semaphorins can act as ligands in active soluble forms, regulating cancer progression via autocrine and paracrine to activate signal transduction in cancer cells or endothelial cells in the tumor microenvironment. Targeting class 4 semaphorins may be a novel strategy for specific cancer therapy. However, the expression of class 4 semaphorins in solid tumors and the responsive pathogenesis are still controversial. Therefore, this review summarizes the specific expression regulation of class 4 semaphorin members in different types of solid tumors and the mechanisms involved in cancer progression.

Disturbed endothelial cell signaling in tumor progression and therapy resistance.

Growth of new blood vessels is considered requisite to cancer progression. Recent findings revealed that in addition to inducing angiogenesis, tumor-derived factors alter endothelial cell gene transcription within the tumor mass but also systemically throughout the body. This subsequently contributes to immunosuppression, altered metabolism, therapy resistance and metastasis. Clinical studies demonstrated that targeting the endothelium can increase the success rate of immunotherapy. Single-cell technologies revealed remarkable organ-specific endothelial heterogeneity that becomes altered by the presence of a tumor. In metastases, endothelial transcription differs remarkably between newly formed and co-opted vessels which may provide a basis for developing new therapies to target endothelial cells and overcome therapy resistance more effectively. This review addresses how cancers impact the endothelium to facilitate tumor progression.

Comparative analysis of the effect of hypoxia in two different tumor cell models shows the differential involvement of PTEN control of proangiogenic pathways.

Hypoxia, low, non-physiological oxygen tension is a key regulator of tumor microenvironment, determining the pathological tumor vascularization. Alleviation of hypoxia through vessel normalization may be a promising therapeutic approach. We aimed to assess the role of low oxygen tension in PTEN-related pathways and proangiogenic response, in vitro, in two different tumor cell lines, focusing on potential therapeutic targets for tumor vessel normalization. Downregulation of PTEN in hypoxia mediates the activation of distinct mechanisms: cytoplasmic pAKT activation in melanoma and pMDM2 modulation in kidney cancer. We show that hypoxia-induced proangiogenic potential was stronger in Renca cells than B16 F10-confirmed by a distinct secretory potential and different ability to affect endothelial cells functions. Therefore, the impact of hypoxia on PTEN-mediated regulation may determine the therapeutic targets and effectiveness of vessel normalization and intrinsic characteristics of cancer cell have to be taken into account when designing treatment.