• BAP1
• Cutaneous melanoma
• Epigenetic reprogramming
• Genomic instability
• PARP inhibition
• PRAME
• UM

• Humans
• Melanoma/genetics
• Melanoma/therapy
• Melanoma/metabolism
• Melanoma/pathology
• Ubiquitin Thiolesterase/genetics
• Ubiquitin Thiolesterase/metabolism
• Genomic Instability
• Tumor Suppressor Proteins/metabolism
• Tumor Suppressor Proteins/genetics
• Immunotherapy
• Antigens, Neoplasm/metabolism
• Antigens, Neoplasm/genetics
• Uveal Neoplasms/genetics
• Uveal Neoplasms/therapy
• Uveal Neoplasms/metabolism
• Uveal Neoplasms/pathology
• Skin Neoplasms/genetics
• Skin Neoplasms/therapy
• Skin Neoplasms/pathology
• Skin Neoplasms/metabolism
• Uveal Melanoma

• Animals
• Anti-angiogenesis therapy
• Cell viability
• Glioblastoma
• Human umbilical vein endothelial cells

• Humans
• Animals
• Human Umbilical Vein Endothelial Cells
• Angiogenesis Inhibitors/pharmacology
• Zebrafish
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/pathology
• Glioma/pathology
• Glioma/metabolism
• Glioma/drug therapy
• Cell Line, Tumor
• Cell Movement/drug effects
• Rats
• Signal Transduction/drug effects
• Matrix Metalloproteinase 2/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Propionates/pharmacology

• EMT
• cancer
• cell plasticity
• deterioration
• signaling pathway

• Bladder cancer
• TJP1
• VEGFA
• Vascular mimicry

• dna methylation
• melanoma

• Humans
• Cell Line, Tumor
• Melanoma/pathology
• Skin Neoplasms/genetics
• Skin Neoplasms/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Epigenesis, Genetic
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Gene Expression Regulation, Neoplastic
• COUP Transcription Factor II/metabolism

• R01 CA274100 NCI NIH HHS
• P30 CA016087 NCI NIH HHS
• R01 CA202027 NCI NIH HHS
• S10 OD018338 NIH HHS
• P50 CA225450 NCI NIH HHS
• P01 CA206980 NCI NIH HHS
• U54 CA263001 NCI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

• Apatinib
• Vasculogenic mimicry
• copper complexes
• micelles
• nano-composite hydrogels

Around 5–10% of advanced melanoma patients progress early on anti-BRAF targeted therapy and 20–30% respond only with the stabilization of the disease. Presumably, these patients could benefit more from first-line immunotherapy. Resistance to BRAF/MEK inhibitors is generated by genetic and non-genetic factors inherent to a tumor or acquired during therapy. Some of them are well documented as a cause of treatment failure. They are potential predictive markers that could improve patients’ selection for both standard and also alternative therapy as some of them have therapeutic potential. Here, a summary of the most promising predictive and therapeutic targets is presented. This up-to-date knowledge may be useful for further study on implementing more accurate genetic/molecular tests in melanoma treatment.

Melanoma is the most aggressive skin cancer, the number of which is increasing worldwide every year. It is completely curable in its early stage and fatal when spread to distant organs. In addition to new therapeutic strategies, biomarkers are an important element in the successful fight against this cancer. At present, biomarkers are mainly used in diagnostics. Some biological indicators also allow the estimation of the patient’s prognosis. Still, predictive markers are underrepresented in clinics. Currently, the only such indicator is the presence of the V600E mutation in the BRAF gene in cancer cells, which qualifies the patient for therapy with inhibitors of the MAPK pathway. The identification of response markers is particularly important given primary and acquired resistance to targeted therapies. Reliable predictive tests would enable the selection of patients who would have the best chance of benefiting from treatment. Here, up-to-date knowledge about the most promising genetic and non-genetic resistance-related factors is described. These are alterations in MAPK, PI3K/AKT, and RB signaling pathways, e.g., due to mutations in NRAS, RAC1, MAP2K1, MAP2K2, and NF1, but also other changes activating these pathways, such as the overexpression of HGF or EGFR. Most of them are also potential therapeutic targets and this issue is also addressed here.

(1) Background: Their unique structure and electron deficiency have brought fullerenes into the focus of research in many fields, including medicine. The hyper-harmonized hydroxylated fullerene water complex (3HFWC) formulation has solved the limitations of the poor solubility and bioavailability of fullerenes. To achieve better antitumor activity, 3HFWC was combined with short-term irradiation of cells with hyperpolarized light (HPL) generated by the application of a nanophotonic fullerene filter in a Bioptron^® device. The benefits of HPL were confirmed in the microcirculation, wound healing and immunological function. (2) Methods: B16, B16-F10 and A375 melanoma cells were exposed to a wide spectrum of 3HFWC doses and to a single short-term HPL irradiation. (3) Results: Apart from the differences in the redox status and level of invasiveness, the effects of the treatments were quite similar. Decreased viability, morphological alteration, signs of melanocytic differentiation and cellular senescence were observed upon the successful internalization of the nanoquantum substance. (4) Conclusions: Overall, 3HFWC/HPL promoted melanoma cell reprogramming toward a normal phenotype.

Endocan is a soluble dermatan sulfate proteoglycan expressed by endothelial cells and detected in serum/plasma. Its expression is increased in tumors/tumor vessels in several human malignancies, and high expression (high serum/plasma levels or tumor levels) has an adverse prognostic impact in several malignancies. The p14 endocan degradation product can also be detected in serum/plasma, but previous clinical studies as well as previously unpublished results presented in this review suggest that endocan and p14 endocan fragment levels reflect different biological characteristics, and the endocan levels seem to reflect the disease heterogeneity in acute leukemia better than the p14 fragment levels. Furthermore, decreased systemic endocan levels in previously immunocompetent sepsis patients are associated with later severe respiratory complications, but it is not known whether this is true also for immunocompromised acute leukemia patients. Finally, endocan is associated with increased early nonrelapse mortality in (acute leukemia) patients receiving allogeneic stem cell transplantation, and this adverse prognostic impact seems to be independent of the adverse impact of excessive fluid overload. Systemic endocan levels may also become important to predict cytokine release syndrome after immunotherapy/haploidentical transplantation, and in the long-term follow-up of acute leukemia survivors with regard to cardiovascular risk. Therapeutic targeting of endocan is now possible, and the possible role of endocan in acute leukemia should be further investigated to clarify whether the therapeutic strategy should also be considered.

• Acute Disease
• Endothelial Cells/metabolism
• Humans
• Leukemia, Myeloid, Acute
• Neoplasm Proteins/metabolism
• Proteoglycans/metabolism
• Sepsis

• AKT
• CD133
• CRISPR/cas9 knockdown
• melanoma stem cells
• trametinib

• Apoptosis/genetics
• CRISPR-Cas Systems/genetics
• Caspases/metabolism
• Cell Line, Tumor
• Humans
• Melanoma/drug therapy
• Melanoma/genetics
• Melanoma/pathology
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism
• RNA, Small Interfering/pharmacology
• Skin Neoplasms
• Stem Cells/metabolism
• bcl-2-Associated X Protein/metabolism
• Melanoma, Cutaneous Malignant

• 5 R42 ES026908 03 NIEHS NIH HHS
• 1R41ES032435-01 NIEHS NIH HHS
• 1R43GM139439-01 NIGMS NIH HHS

• Biomarker
• Epithelial–mesenchymal transition
• Melanomagenesis
• Vasculogenic mimicry
• mRNA/micro-RNA co-expression

• anti-angiogenesis
• bromophenols
• tube formation
• vasculogenic mimicry

• A549 Cells/drug effects
• Angiogenesis Inhibitors/chemistry
• Angiogenesis Inhibitors/pharmacology
• Animals
• Aquatic Organisms
• Cell Proliferation/drug effects
• Human Umbilical Vein Endothelial Cells/drug effects
• Humans
• Microalgae
• Neovascularization, Physiologic/drug effects
• Phenols/chemistry
• Phenols/pharmacology

• 2017YFE0195000 National Key Research and Development Program of China

The current scientific research direction is development of drugs with a targeted effect on malignant tumors. One of the promising groups is indolocarbazoles and their derivatives, which can initiate various tumor cell death pathways. Russian scientists from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation has developed a new experimental drug form of the original compound LCS 1269 with cytotoxic and antiangiogenic properties, blocking vasculogenic mimicry in tumor. The study aim is the experimental drug form LCS 1269 antitumor activity on models of transplantable mouse tumors B-16 melanoma and Lewis epidermoid lung carcinoma (LLC) with different routes and modes of administration.

Female F1 hybrid mice (C₅₇Bl/₆ x DBA/2) and male and female linear mice C₅₇BL/₆ were used for management of tumor strains. Mice were obtained from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation vivarium. The antitumor effect was assessed by tumor growth inhibition (TGI) and increase of treated animal’s life span (ILS) compared to the control.

The experimental drug form showed high antitumor activity when administered intravenously once at doses of 100 and 120 mg/kg (TGI = 98–82% and TGI = 95–77%, respectively, ILS = 24%, p < 0.05) on melanoma B-16 mice. On LLC mice, the experimental drug form showed that the intravenous administration route was effective in the range of doses from 60 to 80 mg/kg with a 5 day administration regimen with an interval of 24 h. A dose of 70 mg/kg had maximum effect at the level of TGI = 96–77% (p < 0.05) with its retention for 20 days after the end of treatment.

The studies have shown that the new compound LCS 1269 in the original drug form, has a pronounced antitumor activity and significantly reduces the volume of tumor mass both on melanoma B-16 and on LLC. It allows us to recommend continue the search for sensitivity of animal transplantable tumors to LCS 1269.

• Angiogenesis
• Antitumor activity
• Indolocarbazole derivatives
• Inhibitor
• Topoisomerase
• Vasculogenic mimicry

• cancer
• cathepsins
• extracellular matrix
• heparanase
• hyaluronidases
• matrix metalloproteinases
• plasminogen activators

• MIS5045810 European Commission
• MIS5033644 European Commission
• MIS5000432 European Commission

• Angiogenesis
• Lymphangiogenesis
• Melanoma
• Metastasis
• Vasculogenic mimicry

• Rho kinase
• cancer stem cell
• epithelial–mesenchymal transition
• transforming growth factor-β1
• vasculogenic mimicry

Angiogenesis and vasculogenic mimicry (VM) are thought to be the predominant processes ensuring tumor blood supply during the growth and metastasis of glioblastoma (GBM). Celastrol has potential anti-glioma effects, however the mechanisms underlying these effects remain unclarified. Recent studies have shown that the PI3K/Akt/mTOR signaling pathway is closely related to angiogenesis and VM formation. In the present study, we have demonstrated, for the first time, that celastrol eliminated VM formation by blocking this signaling pathway in glioma cells. By the treatment of celastrol, tumor growth was suppressed, tight junction and basal lamina structures in tumor microvasculature were disarranged in U87 glioma orthotopic xenografts in nude mice. Periodic acid Schiff (PAS)-CD31 staining revealed that celastrol inhibited both VM and angiogenesis in tumor tissues. Additionally, celastrol reduced the expression levels of the angiogenesis-related proteins CD31, vascular endothelial growth factor receptor (VEGFR) 2, angiopoietin (Ang) 2 and VEGFA, VM-related proteins ephrin type-A receptor (EphA) 2, and vascular endothelial (VE)-cadherin. Hypoxia inducible factor (HIF)-1α, phosphorylated PI3K, Akt, and mTOR were also downregulated by treatment with celastrol. In vitro, we further demonstrated that celastrol inhibited the growth, migration, and invasion of U87 and U251 cells, disrupted VM formation, and blocked the activity of PI3K, Akt, and mTOR. Collectively, our data suggest that celastrol inhibits VM formation and angiogenesis likely by regulating the PI3K/Akt/mTOR signaling pathway.

• VE-cadherin
• angiogenesis
• celastrol
• glioblastoma
• vasculogenic mimicry

Cancer is a complex disease, and its study requires deep understanding of several biological processes and their regulation. It is an accepted fact that non-coding RNAs are vital components of the regulation and cross-talk among cancer-related signaling pathways that favor tumor aggressiveness and metastasis, such as neovascularization, angiogenesis, and vasculogenic mimicry. Both long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) have been described as master regulators of cancer on their own; yet there is accumulating evidence that, besides regulating mRNA expression through independent mechanisms, these classes of non-coding RNAs interact with each other directly, fine-tuning the effects of their regulation. While still relatively scant, research on the lncRNA-miRNA-mRNA axis regulation is growing at a fast rate, it is only in the last 5 years, that lncRNA-miRNA interactions have been identified in tumor-related vascular processes. In this review, we summarize the current progress of research on the cross-talk between lncRNAs and miRNAs in the regulation of neovascularization, angiogenesis and vasculogenic mimicry.

• angiogenesis
• cancer
• long non-conding RNAs
• mRNAs
• miRNAs
• vascularization
• vasculogenic mimecry

• CSC
• Cripto-1
• Nodal
• biomarker
• theranostic agents
• tumor.

• BRAF
• immunotherapy
• melanoma
• targeted therapy

Vasculogenic mimicry (VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors. However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells (CSCs) are positively correlated with VM. In this study, triple-negative breast cancer (TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.

The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples. The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.

CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.

CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.

• ALDH1
• CD133
• Vasculogenic mimicry
• cancer stem-like cells
• triple-negative breast cancer

• RhoA/ROCK signaling pathway
• Sema4D
• cell plasticity
• nonsmall cell lung cancer
• plexinB1
• vasculogenic mimicry

Lysyl oxidase‐like 2 (LOXL2) has shown to promote metastasis and poor prognosis in hepatocellular carcinoma (HCC). Also, we have previously reported that vasculogenic mimicry (VM) is associated with invasion, metastasis and poor survival in HCC patients. In the present study, we investigated molecular function of LOXL2 in HCC and VM. We used the immunohistochemical and CD31/periodic acid‐Schiff double staining to detect the relationship between LOXL2 and VM formation. We performed the gain and loss of function studies and analysed the migratory, invasion and tube formation in HCC cell lines. We analysed the function of LOXL2 in VM formation and HCC metastasis both in vitro and in vivo. We have showed that LOXL2 was overexpression in HCC and was positively correlated with tumour grade, metastasis, VM formation and poor survival in 201 HCC patients. Secondly, our studies have showed that LOXL2 overexpression in HCC cells significantly promoted migration, invasion and tube formation. Finally, we found that LOXL2 may increase SNAIL expression, thereby enabling VM. Our study indicated that LOXL2 may promote VM formation and tumour metastasis by collaborating with SNAIL in HCC. What's more, the overexpression of LOXL2 indicated a poor prognosis in HCC patients.

• angiogenesis
• cell polarity protein
• prognosis
• tumour metastasis
• tumour progression

• Collagen
• Ephrin A2
• Keratinocyte
• Scarring
• Wound repair

• Animals
• Cell Engineering/instrumentation
• Humans
• Lab-On-A-Chip Devices
• Neoplasms/genetics
• Neoplasms/pathology

• R01 CA196018 NCI NIH HHS
• R01 HL136141 NHLBI NIH HHS
• U19 AI116482 NIAID NIH HHS

Tumor cells transfer into endothelial cells by epithelial–endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial–mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear.

Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed.

This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors.

PAR1 promotes EET through Twist1 in HCC.

The online version of this article (10.1186/s13046-018-0858-4) contains supplementary material, which is available to authorized users.

• Epithelial–endothelial transition
• Hepatocellular carcinoma
• Protease-activated receptor-1
• Twist1
• Vasculogenic mimicry

• cancer biomarker
• cancer plasticity
• cancer therapy
• combination therapy
• endogenous retroviruses
• reprogramming
• stemness
• tumor microenvironment

The zinc finger E‐box‐binding homeobox 1 (ZEB1) induced the epithelial–mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid–Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1‐induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT‐related and CSC‐associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p‐Src⁵²⁷ level but not p‐Src⁴¹⁶ level, while ZEB1 knockdown also down‐regulated the level of p‐Src⁵²⁷ in PC3 and DU‐145 cells. PP2 treatment also significantly reduced the expression of VE‐cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression.

• CSC
• EMT
• ZEB1
• prostate cancer
• vasculogenic mimicry

Vasculogenic mimicry (VM) is a functional microcirculation pattern in malignant tumors accompanied by endothelium-dependent vessels and mosaic vessels. VM has been identified in more than 15 solid tumor types and is associated with poor differentiation, late clinical stage and poor prognosis. Classic anti-angiogenic agents do not target endothelium-dependent vessels and are not efficacious against tumors exhibiting VM. Further insight into the molecular signaling that triggers and promotes VM formation could improve anti-angiogenic therapeutics. Recent studies have shown that cancer stem cells (CSCs) and epithelium-to-endothelium transition (EET), a subtype of epithelial-to-mesenchymal transition (EMT), accelerate VM formation by stimulating tumor cell plasticity, remodeling the extracellular matrix (ECM) and connecting VM channels with host blood vessels. VM channel-lining cells originate from CSCs due to expression of EMT inducers such as Twist1, which promote EET and ECM remodeling. Hypoxia and high interstitial fluid pressure in the tumor microenvironment induce a specific type of cell death, linearly patterned programmed cell necrosis (LPPCN), which spatially guides VM and endothelium-dependent vessel networks. This review focuses on the roles of CSCs and EET in VM, and on possible novel anti-angiogenic strategies against alternative tumor vascularization.

• LPPCN
• cancer stem cells
• epithelial-to-endothelial transition
• hypoxia
• vasculogenic mimicry

Tumors contain a sub-population of self-renewing and expanding cells known as cancer stem cells (CSCs). Putative CSCs were isolated from human melanoma cells of a different aggressiveness, Hs294T and A375 cell lines, grown under hypoxia using “sphere-forming assay”, CD133 surface expression and migration ability. We found that a cell sub-population enriched for P1 sphere-initiating ability and CD133 expression also express larger amount of VEGF-R2. Etoposide does not influence phenotype of this sub-population of melanoma cells, while a combined treatment with Etoposide and Bevacizumab significantly abolished P1 sphere-forming ability, an effect associated with apoptosis of this subset of cells. Hypoxic melanoma cells sorted for VEGF-R2/CD133 positivity also undergo apoptosis when exposed to Etoposide and Bevacizumab. When Etoposide and Bevacizumab-treated hypoxic cells were injected intravenously into immunodeficient mice revealed a reduced capacity to induce lung colonies, which also appear with a longer latency period. Hence, our study indicates that a combined exposure to Etoposide and Bevacizumab targets melanoma cells endowed with stem-like properties and might be considered a novel approach to treat cancer-initiating cells.

• CD133/VEGF-R2+ melanoma cells
• Etoposide-Bevacizumab cooperation
• cancer stem-like trait
• human melanoma A375 and Hs294T lines

Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma (HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin (CCO) and cancer-propagating cells, known as hepatic cancer stem cell (HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells (CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.

• Cancer stem cell
• Liver progenitor cell
• Liver stem progenitor cell
• Stemness
• Plasticity
• Cancer cell of origin
• Cancer stem cells subpopulations

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/metabolism
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Disease Models, Animal
• Epigenesis, Genetic
• Epithelial-Mesenchymal Transition
• Hepatocytes/drug effects
• Hepatocytes/pathology
• Humans
• Liver/cytology
• Liver/pathology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Regeneration
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/physiology
• Signal Transduction
• Tumor Microenvironment/genetics

High mobility group protein A2 (HMGA2) is a transcription factor that plays an important role in the invasion and metastasis of gastric carcinoma (GC). The term vasculogenic mimicry (VM) refers to the unique ability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. However, the relationship between HMGA2 and VM formation remains unclear. In the present study, we examined concomitant HMGA2 expression and VM in 228 human GC samples and 4 GC cell lines. Our data indicate that HMGA2 is not only significantly associated with VM formation but also influences the prognosis of patients with gastric carcinoma. Overexpression of HMGA2 significantly increased cell motility, invasiveness, and VM formation both in vitro and in vivo. A luciferase reporter assay, Co-IP and ChIP demonstrated that HMGA2 induced the expression of Twist1 and VE-cadherin by binding to the Twist1 promoter. Moreover, we observed a decrease in VE-cadherin following Twist1 knockdown in cells overexpressing HMGA2. This study indicates that HMGA2 promotes VM in GC via Twist1-VE-cadherin signalling and influences the prognosis of patients with GC.

• Cancer stem cells
• Embryogenesis
• Nodal
• Pluripotency

• Genomics
• Immunotherapy
• Melanoma
• Metastasis
• Target therapy

• Animals
• Antigens, CD/metabolism
• Biopsy
• Cadherins/metabolism
• Cell Line, Tumor
• Cohort Studies
• DNA Copy Number Variations
• Female
• Humans
• Keratins/metabolism
• Lung/pathology
• Lung Neoplasms/blood supply
• Lung Neoplasms/genetics
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Male
• Mice
• Middle Aged
• Mutation
• Neoplastic Cells, Circulating/metabolism
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/pathology
• Single-Cell Analysis
• Small Cell Lung Carcinoma/blood supply
• Small Cell Lung Carcinoma/genetics
• Small Cell Lung Carcinoma/mortality
• Small Cell Lung Carcinoma/pathology
• Tumor Suppressor Protein p53/genetics
• Xenograft Model Antitumor Assays

• R33 CA173373 NCI NIH HHS
• 20465 Cancer Research UK
• 19278 Cancer Research UK
• R37 CA059702 NCI NIH HHS
• 15675 Cancer Research UK

• Bleomycin
• HSV-thymidine kinase
• Interferon-β
• Melanoma
• Spheroids

To characterize the contributions of Dickkopf‐1 (DKK1) towards the induction of vasculogenic mimicry (VM) in non‐small cell lung cancer (NSCLC), we evaluated cohorts of primary tumours, performed in vitro functional studies and generated xenograft mouse models. Vasculogenic mimicry was observed in 28 of 205 NSCLC tumours, while DKK1 was detected in 133 cases. Notably, DKK1 was positively associated with VM. Statistical analysis showed that VM and DKK1 were both related to aggressive clinical course and thus were indicators of a poor prognosis. Moreover, expression of epithelial‐mesenchymal transition (EMT)‐related proteins (vimentin, Slug, and Twist), cancer stem‐like cell (CSC)‐related proteins (nestin and CD44), VM‐related proteins (MMP2, MMP9, and vascular endothelial‐cadherin), and β‐catenin‐nu were all elevated in VM‐positive and DKK1‐positive tumours, whereas the epithelial marker (E‐cadherin) was reduced in the VM‐positive and DKK1‐positive groups. Non‐small cell lung cancer cell lines with overexpressed or silenced DKK1 highlighted its role in the restoration of mesenchymal phenotypes and development of CSC characteristics. Moreover, DKK1 significantly promotes NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that DKK1 enhances the growth of transplanted human tumours cells, as well as increased VM formation, mesenthymal phenotypes and CSC properties. Our results suggest that DKK1 can promote VM formation via induction of the expression of EMT and CSC‐related proteins. As such, we feel that DKK1 may represent a novel target of NSCLC therapy.

• DKK1
• cancer stem-like cell
• epithelial-mesenchymal transition
• non-small cell lung cancer
• vasculogenic mimicry