Open Access

Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review)

  • Authors:
    • Xin Li
    • Zhong Lu
  • View Affiliations

  • Published online on: May 5, 2022     https://doi.org/10.3892/ol.2022.13319
  • Article Number: 198
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Lung adenocarcinoma (LUAD) has a high morbidity and mortality rate worldwide, and its growth and metastasis require angiogenesis. The density of microvessels in LUAD is positively correlated with metastasis and recurrence. Von Willebrand factor (VWF) is a multifunctional glycoprotein in blood plasma. Recent evidence shows that VWF inhibits angiogenesis through regulation of angiopoietin‑2 (Ang‑2) and integrin αvβ3. LUAD patients exhibit an increase in the plasma VWF/ADAMTS‑13 ratio. Gene expression profiles of LUAD tissues indicate that VWF is differentially expressed in LUAD tissues compared to normal tissues. GATA binding protein 3 (GATA3) transcription factor may mediate VWF expression in LUAD. In this review, we summarize the role of VWF in LUAD and its regulatory mechanisms. We also discuss the potential of VWF as a diagnostic indicator and therapeutic target of LUAD.

Introduction

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC), which accounts for approximately 40% of all lung cancer (1). The two most common NSCLC histologic types are LUAD and lung squamous cell carcinoma (LUSC) (2). LUAD cells develop from small airway epithelial cells and the most distal epithelial cells of the lung (3). From adenocarcinoma in situ to minimally invasive adenocarcinoma to overt invasive adenocarcinoma, LUAD progresses in stages (4). In addition, LUAD cells may easily invade the walls of blood vessels and lymphatic vessels and thus metastasize, resulting in poor patient prognosis (5). Although surgical resection, radiation therapy and immunotherapy have made great progress in recent years, the 5-year relative overall survival rate of LUAD patients is approximately 18% (6).

Angiogenesis occurs mainly at the expanding borders of tumor cells in primary LUAD in a hypoxic environment (7). In hypoxic conditions, tumor cells produce and secrete pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF), which activate endothelial cells (ECs) (8). Coincidentally, proliferative ECs have been observed near the alveolar microvasculature. Furthermore, both ECs and tumor cells secrete matrix metalloproteinases (MMPs), which degrade the extracellular matrix (ECM) and basement membranes. Primary sprouts form tubes and then capillary loops, which are followed by pericyte recruitment, synthesis of a new basement membrane, and vessel maturation (9). Low dose of cadmium (Cd) may promote angiogenesis through upregulation of VEGF expression and secretion and promote the development of LUAD (10). In addition, reducing VEGF signaling may effectively inhibit the development of LUAD (11).

Anti-angiogenic drugs that inhibit VEGF signaling pathways, such as ramucirumab and bevacizumab, have been considered a promising option for patients with advanced NSCLC (including LUAD) (12). However, some side effects such as proteinuria, hypertension, and hand and foot syndrome often accompany the treatment with angiogenesis inhibitors that include sorafenib, bevacizumab, and ramucirumab (13,14).

Recently, Starke et al (15) demonstrated that von Willebrand factor (VWF) regulates angiogenesis. The VWF is a component of hemostasis, promoting the binding of platelets and ECs at the site of vascular injury. VWF recruits and tethers platelets at sites of vascular injury, facilitating platelet aggregation (16). In addition, VWF acts as a protective carrier molecule for procoagulant factor VIII (FVIII). Thrombotic thrombocytopenic purpura (TTP), a deadly disease characterized by widespread deposition of VWF and platelet-rich thrombi in the microvasculature (17), is caused by a lack of VWF-specific metalloprotease ADAMTS-13 [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; also known as VWF-cleaving protease (VWFCP)] (18). von Willebrand disease (VWD) is caused by lack of VWF. Knockdown of VWF expression in ECs leads to increased migration and proliferation in response to VEGF (15). This may be consistent with the clinical observation that vascular malformations can cause angiodysplasia in certain patients with VWD. VWF may reduce the migration and proliferation of VEGFR-2-dependent ECs by inhibiting angiopoietin-2 (Ang-2) release and increasing integrin αvβ3 (15).

VWF

Structure of VWF

The domains of VWF are ordered symmetrically as follows: D1-D2-D'D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK (19) (Fig. 1). The D regions are divided into smaller lobes or modules: the D3, D2, and D1 domains are divided into E, TIL, C8, and VWD modules, respectively (19). D', on the other hand, only has the subdomains TIL' and E (19).

Function of VWF

By tethering platelets to areas of endothelial injury and acting as a carrier for coagulation factor VIII, VWF promotes hemostasis. In addition, other functions of VWF have been identified, including immune response (20), tumor metastasis (21), and leukocyte recruitment (22). Recent evidence suggests the potential clinical detection value and potential prognostic value of plasma VWF in patients with acute myocardial infarction (23,24), type 2 diabetes mellitus with cardiovascular complications (25) and coronary artery disease with major adverse cardiovascular events (26). In addition, the results of in vivo and in vitro research suggest that VWF controls angiogenesis and that deficiency of VWF leads to increased angiogenesis (27).

Plasma VWF levels are higher in patients presenting with several types of cancer (28,29). Elevated VWF remains an independent predictor of venous thrombosis in cancer patients after adjusting for patient-related factors (30,31). Higher VWF levels in cancer patients are associated with cancer progression and metastasis (21). Endothelial secretion of VWF contributes to the adhesion and transendothelial migration of breast cancer cells (32). Furthermore, new evidence reveals that VWF regulates tumor cell proliferation and apoptosis (32).

Expression of VWF in LUAD

Plasma VWF and VWF/ADAMTS-13 ratios were found to be significantly increased in patients with advanced NSCLC (including LUAD and LUSC), while the levels of ADAMTS-13 were decreased (28). ADAMTS-13 cleaves VWF in blood in the A2 domain. Furthermore, a marked increase in the VWF/ADAMTS-13 ratio is associated with fibrinogen, D-dimers and coagulation factor VIII (28). ECs of certain microvessels and small vessels in the lung express abundant VWF mRNA. The alveolar-capillary ECs do not express VWF (33). Conversely, other vessels, including the larger vessels, arterioles and bronchial capillaries in the lung, consistently express VWF (33). Xu et al (34) discovered that VWF was overexpressed in tumor vessels of LUAD compared to vessels of adjacent tissues. Consistently, VWF expression was found to be elevated in ECs of transplanted mouse LUAD tissues and fresh human LUAD tissues (34). Similarly, Jin et al (33) discovered that VWF expression is elevated in normal alveolar-capillary ECs near areas of EC germination and tumor invasion. Meanwhile, the cytoplasm of capillary ECs was enlarged and had increased Weibel-Palade bodies (WPBs), which contain VWF, Ang-2, and other angiogenesis mediators (33). However, alveolar-capillary ECs in LUAD developed new reactivity to VWF (35). The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) dataset GSE43458 were used to explore differentially co-expressed genes between LUAD and normal tissues (36). The VWF expression was downregulated in LUAD compared to normal tissue (36).

Transcription factors regulate gene expression of VWF

VWF expression is restricted to ECs and macrophages. The VWF gene sits on the short arm of chromosome 12, spanning ~178 kb. The transcription factors GATA3, ERG, and YY1 have been shown to act as regulators of VWF transcription (37,38) (Fig. 2).

ETS-related gene

The ETS-related gene (ERG) is an ETS family transcription factor specifically expressed in ECs (39), and regulates a series of EC-specific genes (40). By binding with the −56 ETS motif of the VWF promoter, ERG maintains basal expression of VWF (37). In addition, ERG mediates cadmium (Cd)-mediated VWF expression, suggesting that ERG is involved in the transcriptional control of VWF in pathological situations (41). However, the protein and mRNA levels of ERG were unchanged with A549-derived conditioned medium (CM) (34).

GATA3

GATA protein 3 (GATA3) is a transcription factor that belongs to the zinc finger protein family and can recognize (A/T)GATA(A/G) and related sequences. In vivo research has shown that loss of GATA-1 expression in megakaryocytes causes decreased levels of VWF mRNA (42). A GATA-binding motif can be found in the VWF promoter at position +220 (38). Furthermore, GATA3 expression was found to be increased in A549-CM co-cultured human umbilical vein ECs by binding GATA3 to the +220 GATA binding motif in the VWF promoter (34). Therefore, GATA3 may upregulate VWF expression in LUAD (34).

Yin Yang 1

Yin Yang 1 (YY1) is a ubiquitous transcription factor that has both activating and repressive effects. The AATGG sequence is shown to the core consensus binding site of transcription factor YY1 (43). A region in intron 51 of the VWF gene is DNase I hypersensitive (HSS)-specific in non-endothelial cells and interacts with a specific complex of endothelial and non-endothelial cells containing YY1 (43). In addition, the HSS sequence of intron 51 of the VWF gene contains a cis-acting element that is required for VWF gene transcription in a subpopulation of lung ECs (43).

In addition, other transcription factors regulate VWF promoter activity (Fig. 2). Octamer-binding protein (OCT) and nuclear factor-I (NFI) inhibits VWF promoter activity, whereas histone H1-like protein increases promoter activity (44). The nuclear factor (NF)-κB binding site located at −1793 of the VWF promoter inhibits VWF transcription (45). In addition, trans-acting factor nuclear factor Y (NFY) has been confirmed to be both a repressor and an activator of the VWF promoter (44).

Synthesis and secretion of VWF

The biosynthesis of VWF includes several posttranslational modifications in ECs and megakaryocytes (46). The polypeptide of VWF contains 741 characteristic amino acid residues, 22 amino acid long signal peptides, and 2,050 amino acid residue long mature polypeptides (46). In the endoplasmic reticulum, VWF is a dimer (called pro-VWF) through disulfide bonds. Thereafter, this dimer is transported to the Golgi, and it is multimerized through a disulfide bond between the D'D3 structural domains. Subsequently, VWF multimers form tubules and are stored in Weibel-Palade bodies (WPBs) (47).

VWF is secreted through two main pathways. One is regulatory and responds to secretion, and the other is continuous and does not require cellular stimulation (46). Secretion of VWF from specialized storage granules, called WPBs, is triggered by several substances (48). When WPBs are stimulated by a variety of substances such as histamine, thrombin, and phorbol myristate acetate, they release amounts of ultra-large VWF. Once released, they are cleaved in the A2 domain by ADAMTS-13. Thus, VWF circulates in plasma in the form of a series of multimers ranging in size from 500 to 20,000 kDa (42). Plasma VWF is almost exclusively derived from endothelial secretion, and VWF secreted into the subendothelium has a role in EC adhesion and extracellular matrix binding (49).

VWF regulates angiogenesis of LUAD

Inhibition of VWF expression in ECs with short interfering RNA leads to increased angiogenesis in vitro, increased VEGFR-2-dependent migration and proliferation, along with increased Ang-2 release and decreased integrin αvβ3 levels (15). VWF may negatively regulate VEGF-dependent angiogenesis through pathways involving Ang-2 and integrin αvβ3 (50).

Integrin αvβ3

The VWF may regulate angiogenesis and vascular homeostasis by binding integrin αvβ3 (51). Under certain conditions, integrin αvβ3 can inhibit VEGFR-2 activity and downstream signaling to suppress angiogenesis (52). The absence of VWF in ECs leads to integrin αvβ3 expression decrease, which may cause VEGFR-2 signaling increase (53). Interestingly, VWF also interacts with integrin αvβ3 on vascular smooth muscle cells via the Notch signaling pathway (54). However, pharmacological inhibition of integrin αvβ3 inhibits blood vessel generation in experimental models (55). Thus, integrin αvβ3 may have a bimodal effect in regards to angiogenesis, which acts as an activator or an inhibitor depending on the stage of angiogenesis and the different extracellular matrix ligands.

Weibel-Palade body proteins: Angiopoietin-2

VWF may promote the formation of WPBs, which contain angiopoietin-2 (Ang-2) and VWF (56). Reduced or dysfunctional VWF leads to a reduction in WPBs, resulting in the component release of WPB components such as Ang-2 (56). Barton et al found an increase in Ang-2 in VWF-deficient ECs in vitro (57). This has now been confirmed in vivo, with a significant increase in Ang-2 levels in the brains of Vwf −/− mice (58). In addition, the binding of Ang-2 to its receptor Tie-2 can act synergistically with VEGFR-2 signaling to promote angiogenesis (59). Excessive and dysregulated VEGF signaling can lead to the formation of fragile and leaky blood vessels (60). For example, patients with VWD show a high prevalence of gastrointestinal vascular malformations.

In addition to integrin αvβ3 and Ang-2, VWF also interacts with galectin-3 (61), galectin-1, and insulin-like growth factor binding protein-7 (62). Meanwhile, the interaction of VWF with GPIba has been reported to affect cell migration.

The angiogenic factors VEGF and fibroblast growth factor-2 (FGF-2), which are abundant in the tumor microenvironment, have been shown to upregulate VWF expression. Treatment with bevacizumab, an anti-VEGF, has been demonstrated to lower VWF levels in the blood (63). In vitro, VWF binds to VEGF-A through the heparin-binding domain (HBD) within the VWF A1 domain (64). Incorporation of the A1-HBD domain of VWF protein into fibrin matrices enables sequestration and slows release of incorporated VEGF-A (64).

Discussion

Plasma VWF and the VWF/ADAMTS-13 ratio have been found to be substantially increased, whereas ADAMTS-13 levels were found to be decreased in patients with advanced NSCLC (28). Tumor cells directly induce activation of ECs, leading to WPB extravasation and release of ultra-large VWF multimers (65). Ultra-large VWF multimers are discharged into the plasma, where the plasma VWF-cleaving protease ADAMTS-13 rapidly degrades them into smaller VWF multimers (66). Smaller VWF multimers are more rapidly cleared from the circulation than ultra-large VWF (67). Increased ultra-large VWF in plasma disrupts the balance between VWF and ADAMTS-13 levels, resulting in an increased VWF/ADAMTS-13 ratio (68). The VWF/ADAMTS-13 ratio has been used to diagnose hypercoagulability caused by an imbalance in VWF secretion and ADAMTS-13 in patients with organ failure (69). In patients with advanced NSCLC, a marked increase in the VWF/ADAMTS-13 ratio was found to be positively correlated with D-dimers, fibrinogen and coagulation factor VIII (28). Therefore, elevated VWF/ADAMTS-13 levels implicate a highly thrombotic state, resulting in thrombosis in cancer patients. VWF/ADAMTS-13 in plasma has the potential to be used as a marker of prognosis in patients with LUAD.

VWF was found to be preferentially overexpressed in tumor vessels of LUAD compared to vessels of adjacent tissues (34). Consistently, overexpression of VWF was found in ECs of transplanted mouse LUAD tissues and fresh human LUAD tissues (34). However, VWF was recently found to be expressed in normal lung tissue, but low or undetectable levels were found in LUAD tissue (36). Furthermore, survival analysis showed that LUAD patients with low VWF expression in tissues had a poorer prognosis (70). Thus, VWF may be differentially expressed in different stages of LUAD. The association between VWF levels and LUAD staging may be explored and potentially used for prognosis.

The mechanism of VWF regulation of tumor angiogenesis in LUAD has not been elucidated. VWF may act as a negative regulator of VEGF-dependent angiogenesis through pathways involving integrin αvβ3 and Ang-2 (50). In addition to integrin αvβ3 and Ang-2, VWF interacts with galectin-3 and galectin-1, which are involved in the control of angiogenesis. Supplementation with VWF analogs may inhibit tumor angiogenesis in LUAD. There are several medications available to elevate VWF with no significant side effects. Desmopressin (dDAVP) is a treatment for patients with VWD and stimulates the release of endogenous VWF into the plasma (71). MINIRIN® (dDAVP) is supplied by Ferring/Valeas (71). The recommended dosage is 0.3 µg/kg by slow i.v. infusion or fixed doses of 150 µg in children and 300 µg in adults by intranasal spray (71). A human recombinant VWF (rVWF), vonicog alfa, was found to increase VWF levels in VWD patients, making treatment independent of plasma supply (72). rVWF is a purified glycoprotein synthesized in a genetically engineered CHO cell line (72). The doses of 50 and 80 U/kg VWF have been used for evaluation (72). These drugs may treat LUAD by increasing VWF in the blood to inhibit tumor angiogenesis. Paradoxically, VWF has the potential to promote tumor metastasis (21). Tumor cells of nonendothelial origin may acquire de novo VWF expression and show enhanced EC adhesion and extravasation (21). In addition, tumor cells directly induce EC activation resulting in WPB exocytosis and the release of ultra-large VWF strings (21). VWF binds to platelets via GPIbα and GPIIb/IIIa receptors and to tumor cells via GPIIb/IIIa receptors or their semi-homologous twin integrin αvβ3 (65), and, therefore, may tether platelets and tumor cells along the endothelium (21). This interaction may increase tumor cell adhesion to the vascular endothelium and promote extravasation (21). The balance of the potential benefits and risks of VWF treatment on LUAD should be carefully considered. Given that VWF inhibits angiogenesis and thus LUAD growth, VWF supplementation may achieve therapeutic effects in LUAD. However, VWF may also promote tumor metastasis. VWF supplementation is not recommended for patients with early-stage LUAD to avoid the risk of tumor metastasis. Anti-angiogenesis therapy is essential for patients with advanced LUAD, thus VWF supplementation may be attempted together with conventional chemotherapy.

Acknowledgements

Not applicable.

Funding

This study is supported by Shandong Provincial Administration of Traditional Chinese Medicine (grant no. 2017-218).

Availability of data and materials

Not applicable.

Authors' contributions

ZL conceived and designed the review. XL wrote the first draft. XL and ZL participated in writing of the manuscript. All authors contributed to the article and read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

LUAD

lung adenocarcinoma

VWF

von Willebrand factor

Ang-2

angiopoietin-2

ECs

endothelial cells

NSCLC

non-small cell lung cancer

VEGF

vascular endothelial growth factor

VEGFR-2

endothelial growth factor receptor-2

LUSC

lung squamous cell carcinoma

VWD

von Willebrand disease

WPBs

Weibel-Palade bodies

ERG

ETS-related gene

Cd

cadmium

OCT

octamer-binding protein

NFI

nuclear factor-I

NF-κB

nuclear factor-κB

NFY

nuclear factor Y

dDAVP

desmopressin

r VWF

recombinant VWF

YYI

Yin Yang 1

References

1 

Kuhn E, Morbini P, Cancellieri A, Damiani S, Cavazza A and Comin CE: Adenocarcinoma classification: Patterns and prognosis. Pathologica. 110:5–11. 2018.

2 

Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Hynds RE, Ben Aissa A, Gowers KHC, Watkins TBK, Bosshard-Carter L, Rowan AJ, Veeriah S, Wilson GA, Quezada SA, Swanton C, et al: Expansion of airway basal epithelial cells from primary human non-small cell lung cancer tumors. Int J Cancer. 143:160–166. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Ding Y, Zhang L, Guo L, Wu C, Zhou J, Zhou Y, Ma J, Li X, Ji P, Wang M, et al: Comparative study on the mutational profile of adenocarcinoma and squamous cell carcinoma predominant histologic subtypes in Chinese non-small cell lung cancer patients. Thorac Cancer. 11:103–112. 2020. View Article : Google Scholar : PubMed/NCBI

5 

Wang X and Adjei AA: Lung cancer and metastasis: New opportunities and challenges. Cancer Metastasis Rev. 34:169–171. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Liu B and Wei C: Hypoxia induces overexpression of CCL28 to recruit treg cells to enhance angiogenesis in lung adenocarcinoma. J Environ Pathol Toxicol Oncol. 40:65–74. 2021. View Article : Google Scholar

8 

Zahn LM: Effects of the tumor microenvironment. Science. 355:1386–1388. 2017. View Article : Google Scholar

9 

Lugano R, Ramachandran M and Dimberg A: Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell Mol Life Sci. 77:1745–1770. 2020. View Article : Google Scholar

10 

Liu F, Wang B, Li L, Dong F, Chen X, Li Y, Dong X, Wada Y, Kapron CM and Liu J: Low-dose cadmium upregulates VEGF expression in lung adenocarcinoma cells. Int J Environ Res Public Health. 12:10508–10521. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Liu J, Li Y, Dong F, Li L, Masuda T, Allen TD and Lobe CG: Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice. Biochem Biophys Res Commun. 463:1230–1236. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Frezzetti D, Gallo M, Maiello MR, D'Alessio A, Esposito C, Chicchinelli N, Normanno N and De Luca A: VEGF as a potential target in lung cancer. Expert Opin Ther Targets. 21:959–966. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 383:31–39. 2014. View Article : Google Scholar

14 

Kurzrock R and Stewart DJ: Exploring the Benefit/Risk associated with antiangiogenic agents for the treatment of non-small cell lung cancer patients. Clin Cancer Res. 23:1137–1148. 2017. View Article : Google Scholar : PubMed/NCBI

15 

Starke RD, Ferraro F, Paschalaki KE, Dryden NH, McKinnon TA, Sutton RE, Payne EM, Haskard DO, Hughes AD, Cutler DF, et al: Endothelial von Willebrand factor regulates angiogenesis. Blood. 117:1071–1080. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Löf A, Müller JP and Brehm MA: A biophysical view on von Willebrand factor activation. J Cell Physiol. 233:799–810. 2018. View Article : Google Scholar

17 

Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T and Vanhoorelbeke K: Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers. 3:170202017. View Article : Google Scholar : PubMed/NCBI

18 

Sadler JE: Pathophysiology of thrombotic thrombocytopenic purpura. Blood. 130:1181–1188. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Zhou YF, Eng ET, Zhu J, Lu C, Walz T and Springer TA: Sequence and structure relationships within von Willebrand factor. Blood. 120:449–458. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Chen J, Schroeder JA, Luo X and Shi Q: The impact of von Willebrand factor on factor VIII memory immune responses. Blood Adv. 1:1565–1574. 2017. View Article : Google Scholar : PubMed/NCBI

21 

O'Sullivan JM, Preston RJS, Robson T and O'Donnell JS: Emerging roles for von willebrand factor in cancer cell biology. Semin Thromb Hemost. 44:159–166. 2018. View Article : Google Scholar

22 

Kawecki C, Lenting PJ and Denis CV: von Willebrand factor and inflammation. J Thromb Haemost. 15:1285–1294. 2017. View Article : Google Scholar

23 

Wang X, Zhao J, Zhang Y, Xue X, Yin J, Liao L, Xu C, Hou Y, Yan S and Liu J: Kinetics of plasma von Willebrand factor in acute myocardial infarction patients: A meta-analysis. Oncotarget. 8:90371–90379. 2017. View Article : Google Scholar

24 

Li Y, Li L, Dong F, Guo L, Hou Y, Hu H, Yan S, Zhou X, Liao L, Allen TD and Liu JU: Plasma von Willebrand factor level is transiently elevated in a rat model of acute myocardial infarction. Exp Ther Med. 10:1743–1749. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Peng X, Wang X, Fan M, Zhao J, Lin L and Liu J: Plasma levels of von Willebrand factor in type 2 diabetes patients with and without cardiovascular diseases: A meta-analysis. Diabetes Metab Res Rev. 36:e31932020. View Article : Google Scholar : PubMed/NCBI

26 

Fan M, Wang X, Peng X, Feng S, Zhao J, Liao L, Zhang Y, Hou Y and Liu J: Prognostic value of plasma von Willebrand factor levels in major adverse cardiovascular events: A systematic review and meta-analysis. BMC Cardiovasc Disord. 20:722020. View Article : Google Scholar : PubMed/NCBI

27 

Randi AM, Smith KE and Castaman G: von Willebrand factor regulation of blood vessel formation. Blood. 132:132–140. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Guo R, Yang J, Liu X, Wu J and Chen Y: Increased von Willebrand factor over decreased ADAMTS-13 activity is associated with poor prognosis in patients with advanced non-small-cell lung cancer. J Clin Lab Anal. 32:e222192018. View Article : Google Scholar

29 

Marfia G, Navone SE, Fanizzi C, Tabano S, Pesenti C, Abdel Hadi L, Franzini A, Caroli M, Miozzo M, Riboni L, et al: Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma. Cancer Med. 5:1783–1790. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Obermeier HL, Riedl J, Ay C, Koder S, Quehenberger P, Bartsch R, Kaider A, Zielinski CC and Pabinger I: The role of ADAMTS-13 and von Willebrand factor in cancer patients: Results from the vienna cancer and thrombosis Study. Res Pract Thromb Haemost. 3:503–514. 2019. View Article : Google Scholar

31 

Pépin M, Kleinjan A, Hajage D, Büller HR, Di Nisio M, Kamphuisen PW, Salomon L, Veyradier A, Stepanian A and Mahé I: ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. J Thromb Haemost. 14:306–315. 2016. View Article : Google Scholar

32 

Qi Y, Chen W, Liang X, Xu K, Gu X, Wu F, Fan X, Ren S, Liu J, Zhang J, et al: Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction. J Hematol Oncol. 11:1172018. View Article : Google Scholar

33 

Jin E, Ghazizadeh M, Fujiwara M, Nagashima M, Shimizu H, Ohaki Y, Arai S, Gomibuchi M, Takemura T and Kawanami O: Angiogenesis and phenotypic alteration of alveolar capillary endothelium in areas of neoplastic cell spread in primary lung adenocarcinoma. Pathol Int. 51:691–700. 2001. View Article : Google Scholar

34 

Xu Y, Pan S, Liu J, Dong F, Cheng Z, Zhang J, Qi R, Zang Q, Zhang C, Wang X, et al: GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature. Oncotarget. 8:110517–110529. 2017. View Article : Google Scholar

35 

Morishita C, Jin E, Kikuchi M, Egawa S, Fujiwara M, Ohaki Y, Ghazizadeh M, Takemura T and Kawanami O: Angiogenic switching in the alveolar capillaries in primary lung adenocarcinoma and squamous cell carcinoma. J Nippon Med Sch. 74:344–354. 2007. View Article : Google Scholar : PubMed/NCBI

36 

He Y, Liu R, Yang M, Bi W, Zhou L, Zhang S, Jin J, Liang X and Zhang P: Identification of VWF as a novel biomarker in lung adenocarcinoma by comprehensive analysis. Front Oncol. 11:6396002021. View Article : Google Scholar

37 

Liu J, Yuan L, Molema G, Regan E, Janes L, Beeler D, Spokes KC, Okada Y, Minami T, Oettgen P and Aird WC: Vascular bed-specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle. Blood. 117:342–351. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Liu J, Kanki Y, Okada Y, Jin E, Yano K, Shih SC, Minami T and Aird WC: A +220 GATA motif mediates basal but not endotoxin-repressible expression of the von Willebrand factor promoter in Hprt-targeted transgenic mice. J Thromb Haemost. 7:1384–1392. 2010. View Article : Google Scholar

39 

Yuan L, Sacharidou A, Stratman AN, Le Bras A, Zwiers PJ, Spokes K, Bhasin M, Shih SC, Nagy JA, Molema G, et al: RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG. Blood. 118:1145–1153. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Liu F, Liu Q, Yuan F, Guo S and Liu J, Sun Z, Gao P, Wang Y, Yan S and Liu J: Erg mediates downregulation of claudin-5 in the brain endothelium of a murine experimental model of cerebral malaria. FEBS Lett. 593:2585–2595. 2019. View Article : Google Scholar

41 

Wang X, Dong F, Wang F, Yan S, Chen X, Tozawa H, Ushijima T, Kapron CM, Wada Y and Liu J: Low dose cadmium upregulates the expression of von Willebrand factor in endothelial cells. Toxicol Lett. 290:46–54. 2018. View Article : Google Scholar

42 

Stockschlaeder M, Schneppenheim R and Budde U: Update on von Willebrand factor multimers: Focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis. 25:206–216. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Kleinschmidt AM, Nassiri M, Stitt MS, Wasserloos K, Watkins SC, Pitt BR and Jahroudi N: Sequences in intron 51 of the von Willebrand factor gene target promoter activation to a subset of lung endothelial cells in transgenic mice. J Biol Chem. 283:2741–2750. 2008. View Article : Google Scholar : PubMed/NCBI

44 

Nassiri M, Liu J, Kulak S, Uwiera RR, Aird WC, Ballermann BJ and Jahroudi N: Repressors NFI and NFY participate in organ-specific regulation of von Willebrand factor promoter activity in transgenic mice. Arterioscler Thromb Vasc Biol. 30:1423–1429. 2010. View Article : Google Scholar

45 

Harvey PJ, Keightley AM, Lam YM, Cameron C and Lillicrap D: A single nucleotide polymorphism at nucleotide-1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF: Ag levels. Br J Haematol. 109:349–353. 2000. View Article : Google Scholar

46 

Lenting PJ, Christophe OD and Denis CV: von Willebrand factor biosynthesis, secretion, and clearance: Connecting the far ends. Blood. 125:2019–2028. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Zeng J, Shu Z, Liang Q, Zhang J, Wu W, Wang X and Zhou A: Structural basis of Von Willebrand Factor multimerization and tubular storage. Blood. 5–Feb;2022.doi: 10.1182/blood.2021014729. View Article : Google Scholar

48 

van den Biggelaar M, Bierings R, Storm G, Voorberg J and Mertens K: Requirements for cellular co-trafficking of factor VIII and von Willebrand factor to Weibel-Palade bodies. J Thromb Haemost. 5:2235–2242. 2007. View Article : Google Scholar

49 

Lopes da Silva M and Cutler DF: von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells. Blood. 128:277–285. 2016. View Article : Google Scholar : PubMed/NCBI

50 

Randi AM and Laffan MA: Von Willebrand factor and angiogenesis: Basic and applied issues. J Thromb Haemost. 15:13–20. 2017. View Article : Google Scholar

51 

Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G and Cheresh DA: Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 79:1157–1164. 1994. View Article : Google Scholar

52 

Sartori A, Portioli E, Battistini L, Calorini L, Pupi A, Vacondio F, Arosio D, Bianchini F and Zanardi F: Synthesis of Novel c(AmpRGD)-sunitinib dual conjugates as molecular tools targeting the αvβ3 Integrin/VEGFR2 couple and impairing tumor-associated angiogenesis. J Med Chem. 60:248–262. 2017. View Article : Google Scholar : PubMed/NCBI

53 

Somanath PR, Malinin NL and Byzova TV: Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis. 12:177–1185. 2009. View Article : Google Scholar : PubMed/NCBI

54 

Lagrange J, Worou ME, Michel JB, Raoul A, Didelot M, Muczynski V, Legendre P, Plénat F, Gauchotte G, Lourenco-Rodrigues MD, et al: The VWF/LRP4/αVβ3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells. Cardiovasc Res. 118:622–637. 2022. View Article : Google Scholar : PubMed/NCBI

55 

Patsenker E, Popov Y, Stickel F, Schneider V, Ledermann M, Sägesser H, Niedobitek G, Goodman SL and Schuppan D: Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology. 50:1501–1511. 2009. View Article : Google Scholar : PubMed/NCBI

56 

Cossutta M, Darche M, Carpentier G, Houppe C, Ponzo M, Raineri F, Vallée B, Gilles ME, Villain D, Picard E, et al: Weibel-Palade bodies orchestrate pericytes during angiogenesis. Arterioscler Thromb Vasc Biol. 39:1843–1858. 2019. View Article : Google Scholar

57 

Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP and Nikolov DB: Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol. 13:524–532. 2006. View Article : Google Scholar

58 

Xu H, Cao Y, Yang X, Cai P, Kang L, Zhu X, Luo H, Lu L, Wei L, Bai X, et al: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery. Blood. 130:11–22. 2017. View Article : Google Scholar : PubMed/NCBI

59 

Scholz A, Plate KH and Reiss Y: Angiopoietin-2: A multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 1347:45–51. 2015. View Article : Google Scholar

60 

Siveen KS, Prabhu K, Krishnankutty R, Kuttikrishnan S, Tsakou M, Alali FQ, Dermime S, Mohammad RM and Uddin S: Vascular endothelial growth factor (VEGF) signaling in tumour vascularization: Potential and challenges. Curr Vasc Pharmacol. 15:339–351. 2017. View Article : Google Scholar

61 

Saint-Lu N, Oortwijn BD, Pegon JN, Odouard S, Christophe OD, de Groot PG, Denis CV and Lenting PJ: Identification of galectin-1 and galectin-3 as novel partners for von Willebrand factor. Arterioscler Thromb Vasc Biol. 32:894–901. 2012. View Article : Google Scholar

62 

Tamura K, Hashimoto K, Suzuki K, Yoshie M, Kutsukake M and Sakurai T: Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol. 610:61–67. 2009. View Article : Google Scholar

63 

Pace A, Mandoj C, Antenucci A, Villani V, Sperduti I, Casini B, Carosi M, Fabi A, Vidiri A, Koudriavtseva T and Conti L: A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma. J Neurooncol. 138:527–535. 2018. View Article : Google Scholar

64 

Ishihara J, Ishihara A, Starke RD, Peghaire CR, Smith KE, McKinnon TAJ, Tabata Y, Sasaki K, White MJV, Fukunaga K, et al: The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing. Blood. 133:2559–2569. 2019. View Article : Google Scholar : PubMed/NCBI

65 

Bauer AT, Suckau J, Frank K, Desch A, Goertz L, Wagner AH, Hecker M, Goerge T, Umansky L, Beckhove P, et al: von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans. Blood. 125:3153–3163. 2015. View Article : Google Scholar : PubMed/NCBI

66 

Lancellotti S, Sacco M, Basso M and De Cristofaro R: Mechanochemistry of von Willebrand factor. Biomol Concepts. 10:194–208. 2019. View Article : Google Scholar : PubMed/NCBI

67 

Kappler S, Ronan-Bentle S and Graham A: Thrombotic microangiopathies (TTP, HUS, HELLP). Hematol Oncol Clin North Am. 31:1081–1103. 2017. View Article : Google Scholar : PubMed/NCBI

68 

Takaya H, Uemura M, Fujimura Y, Matsumoto M, Matsuyama T, Kato S, Morioka C, Ishizashi H, Hori Y, Fujimoto M, et al: ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child-Turcotte-Pugh score and the Model for End-stage liver disease score. Hepatol Res. 42:459–472. 2012. View Article : Google Scholar : PubMed/NCBI

69 

Claus RA, Bockmeyer CL, Budde U, Kentouche K, Sossdorf M, Hilberg T, Schneppenheim R, Reinhart K, Bauer M, Brunkhorst FM and Lösche W: Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost. 101:239–247. 2009. View Article : Google Scholar

70 

Yang R, Zhou Y, Du C and Wu Y: Bioinformatics analysis of differentially expressed genes in tumor and paracancerous tissues of patients with lung adenocarcinoma. J Thorac Dis. 12:7355–7364. 2020. View Article : Google Scholar : PubMed/NCBI

71 

Federici AB: The use of desmopressin in von Willebrand disease: The experience of the first 30 years (1977–2007). Haemophilia. 14 (Suppl 1):S5–S14. 2008. View Article : Google Scholar

72 

Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, Obermann-Slupetzky O, Chapman M, Fritsch S, Pavlova BG, et al: Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 126:2038–2046. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June-2022
Volume 23 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Li X and Lu Z: Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review). Oncol Lett 23: 198, 2022.
APA
Li, X., & Lu, Z. (2022). Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review). Oncology Letters, 23, 198. https://doi.org/10.3892/ol.2022.13319
MLA
Li, X., Lu, Z."Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review)". Oncology Letters 23.6 (2022): 198.
Chicago
Li, X., Lu, Z."Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review)". Oncology Letters 23, no. 6 (2022): 198. https://doi.org/10.3892/ol.2022.13319