Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth.

Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer.

Background: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular subtypes of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk. Methods: We identified ARHGDIG , ATP1A1 , SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study ( n = 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc)RCC ( n = 306) and stratified by tumours with no, low (1 gene) and high (≥ 2 genes) methylation. Results: Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant ( P -heterogeneity = 0.26). Potassium intake was differentially associated with ccRCC risk ( P -heterogeneity = 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95% CI): 0.60 (0.36-1.01)], but high for tumours with a high methylation index [HR (95% CI): 1.60 (0.96-2.65)]. Risks similarly differed for fluid intake, though not significantly ( P -heterogeneity = 0.54). Conclusions: Our findings suggest for the first time that dietary intakes are differentially associated with ccRCC risk according to molecular subtypes defined by ITM gene-specific promoter methylation.

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies.

PURPOSE: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). FINDINGS: In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. IMPLICATIONS: Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).

Adherence to guideline recommendations for management of clinical T1 renal cancers in the Netherlands: a population-based study.

PURPOSE: For decades, small renal cancers are treated by radical nephrectomy (RN). Current guidelines recommend partial nephrectomy (PN) to preserve renal function and minimize cardiovascular comorbidity. As adherence to guidelines is largely unknown and international comparison to evaluate quality of health care is lacking, an pre-specified guideline evaluation of quality indicators concerning management of cT1 renal cancers was performed. METHODS: We performed a cohort study including patients with cT1 renal cancer between 2010 and 2014, identified through the Netherlands Cancer Registry. Time trends and variation in treatment were described. Factors associated with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses. RESULTS: An increase in nephron-sparing treatment strategies (NSS) of cT1a patients (N total = 2436) was observed; in 2014, 67 % underwent NSS (62 % PN and 5 % thermal ablation). Age, a non-central tumor localization and being treated in a high-volume hospital were associated with PN. Although NSS were applied more frequently over time, the majority (70 %) of cT1b patients (N total = 2205) underwent RN in 2014, mainly performed laparoscopically. Increasing tumor size, tumor localization in the right kidney and being treated in a university hospital were associated with a lower probability of a laparoscopic RN versus open. Treatment in a high-volume hospital was associated with a higher probability of laparoscopic RN. CONCLUSIONS: Dutch patients with cT1 renal cancer are predominantly treated according to current guidelines. Data of this pre-specified quality indicator analysis of a urological national guideline may serve as a model for international comparison of treatment of cT1 renal cancers.

Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours.

BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. RESULTS: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. CONCLUSIONS: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity.

Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.

Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors.

BACKGROUND: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. METHODS: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. RESULTS: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high-fat meal). CONCLUSIONS: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. FUNDING: AstraZeneca.

Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome.

PURPOSE: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival. EXPERIMENTAL DESIGN: We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests. RESULTS: Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001). CONCLUSIONS: CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis.

[Sentinel lymph node procedure in melanoma patients: a staging procedure, not a therapy]. / Schildwachtklierprocedure voor melanoom: niet therapeutisch, maar stagerend.

The definitive results of the MSLT-1 study in melanoma patients were published recently. The sentinel lymph node (SLN) procedure shows no survival benefit compared with observation. The authors reported, however, that there was a survival benefit with "biopsy management" of patients. This statement is based on subgroup analyses that we find to be incorrect for three reasons: (a) patients with a false negative SLN were incorrectly left out of consideration; (b) accelerated failure time latent subgroup analysis is an unproven statistical hypothesis, which was developed on interim data from the MSLT-1 study, and therefore cannot be used as validation; (c) there is a significant difference in terms of the percentage of patients with affected lymph nodes between the SLN group and the observation group. This excess of "prognostic false positive" patients would have incorrectly falsely improved the survival of the SLN group. We concluded that the SLN procedure does not give a survival benefit and that its role in melanoma patients should be for staging purposes and not for therapeutic purposes.

An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors.

PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events. METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety. RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively. CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma.

INTRODUCTION: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. METHODS: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. RESULTS: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. CONCLUSION: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

Safety and efficacy of sequential chemotherapy with carboplatin plus gemcitabine followed by weekly paclitaxel in advanced non-small cell lung cancer.

BACKGROUND: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC. METHODS: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2). RESULTS: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity. CONCLUSION: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.

[The Dutch guideline 'Renal cell carcinoma']. / Nederlandse richtlijn 'Niercelcarcinoom'.

The Dutch guideline 'Renal Cell Carcinoma' has been revised on the basis of new literature. With the assistance of the Netherlands Cancer Registry an assessment was made of the current care for patients with renal cell carcinoma. Renal cell carcinoma is a type of cancer for which knowledge of the genetic basis of the different histological subtypes has led to the development of new targeted therapies. By the introduction of these systemic therapies, histological subtyping of renal cell carcinoma has become more important. Although in the previous guideline cytological or histological diagnosis was recommended to determine the nature of the tumourous process in the kidney, in the revision it is advised to use histological needle biopsies to determine the histological subtype and therefore to provide evidence for the choice of systemic therapy. With modern diagnostic techniques, more patients with smaller tumours are identified. For these tumours, less invasive therapies are recommended in order to preserve as much renal tissue as possible.

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.

PURPOSE: This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states. METHODS: A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment. RESULTS: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. CONCLUSIONS: The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.

VHL and HIF signalling in renal cell carcinogenesis.

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.

Signalling pathways in vasculogenic mimicry.

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.