review article the role of vascular endothelial growth...

Hindawi Publishing CorporationProstate CancerVolume 2013 Article ID 418340 8 pageshttpdxdoiorg1011552013418340

Review ArticleThe Role of Vascular Endothelial Growth Factor inMetastatic Prostate Cancer to the Skeleton

Emma Roberts1 Davina A F Cossigny1 and Gerald M Y Quan12

1 Spinal Biology Research Laboratory University of Melbourne Department of Surgery Austin Health PO Box 5555Heidelberg VIC 3084 Australia

2 Department of Spinal Surgery Austin Health PO Box 5555 Heidelberg VIC 3084 Australia

Correspondence should be addressed to Gerald M Y Quan geraldquanaustinorgau

Received 30 June 2013 Revised 4 November 2013 Accepted 14 November 2013

Academic Editor Manfred Wirth

Copyright copy 2013 Emma Roberts et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Despite the clinical implication andhigh incidence of bone and spinalmetastases themolecularmechanisms behind prostate cancermetastasis to bone and spine are not well understood In this review the molecular mechanisms that may contribute to the highlymetastatic phenotype of prostate cancer are discussed Proangiogenic factors such as vascular endothelial growth factor (VEGF)have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growthof prostate tumour cells in the skeleton The importance of VEGF in the complex process of prostate cancer dissemination to theskeleton is discussed including its role in the development of the bone premetastatic niche metastatic tumour cell recognition ofbone and bone remodeling The expression of VEGF has also been shown to be upregulated in prostate cancer and is associatedwith clinical stage Gleason score tumour stage progression metastasis and survival Due to the multifaceted effect VEGF hason tumour angiogenesis tumour cell proliferation and bone destruction therapies targeting the VEGF pathways have shownpromising clinical application and are being investigated in clinical trials

1 Introduction

The five-year survival rate for prostate cancer is extremelyhigh when confined to the prostate but in the presenceof metastatic disease it is reduced to 33 [1] In Australiaprostate cancer contributes to almost 5of all registeredmaledeaths [2] of whichmore than 80will have developed spinalmetastases during the course of their disease [3ndash5] Once can-cer metastasizes to bone and the vertebral column patientsoften experience intractable pain and neurological deficit dueto pathological fractures spinal instability and metastaticepidural spinal cord compression The neurological sequelaeinclude sensory disturbance motor weakness paralysis andincontinence leading to decreased function inability toambulate and impaired quality of life [5] Treatment optionsinclude radiotherapy hormonal therapy chemotherapeuticagents such as docetaxel cabazitaxel sipuleucel-T and abi-raterone acetate anddecompression and stabilization surgery[6 7] These modalities may be able to extend survival ratesbut are all predominantly palliative with median survivaltime limited from one to two years from the onset of

metastases [5 6] Despite the clinical implication and highincidence of spinal metastasis the molecular mechanismsbehind prostate cancer metastasis to bone and the spineare not well understood Vascular endothelial growth factor(VEGF) is well known to be potent stimulator of angiogenesisin both physiological and pathological conditions and ishighly expressed in most solid tumours including prostatecancer This review discusses the role of VEGF in tumourangiogenesis and bone destruction in metastatic prostatecancer to the spine

2 VEGF and Its Receptors

VEGF is a ligand of the VEGF tyrosine kinase receptorsuperfamily and includes VEGF-A -B -C and -D withsplice variants of VEGF-A resulting in several differentisoforms [8 9] The VEGF family ligands bind to tyrosinekinase receptors VEGFR1 VEGFR2 and VEGFR3 (Figure 1)each receptor containing an extracellular domain of approx-imately 750 amino acid residues arranged within seven

2 Prostate Cancer

Endothelial cell VEGF

VEGF-AVEGF-B (VEGF-C

VEGF-D)

VEGF-CVEGF-D

VEGFR1

NRP-2VEGFR1 and-2

NRP-1VEGFR2 VEGFR2 and-3

HSPGVEGFR3

PI3K

AktPKBp38MAPK

Ras

MAK

ERK

Cell survival

Cell proliferation

VEGF-AVEGF-A

VEGFR2

VEGF-CVEGF-D

NF-120581B

Cell proliferationsurvivaldifferentiationmigration andangiogenesis

Figure 1 VEGF receptor bindingThefivemammalian vascular endothelial growth factors (VEGF-A-D) bind to the receptor tyrosine kinasesVEGF receptor (VEGFR1-3 and co-receptors HSPG NRP-1 and NRP-2) VEGFR-binding leads to the formation of homodimers andorheterodimers Proteolytic cleavage enables VEGF-C and -D to bind VEGFR-2 forming a homodimer The binding and activation of VEGFR-2 lead to downstream signaling of the PI3K MAPK and Ras pathways which promote cell survival proliferation differentiation migrationand angiogenesis

immunoglobulin-like folds [10] Additionally heparin sul-phate proteoglycans (HSPGs) as well as neuropilins (NRP-1and NRP-2) can act as coreceptors for VEGF and promoteVEGFR activation [11 12] Each VEGF family member bindswith differential affinity for their receptors for exampleVEGFR2 is primarily activated by VEGF-A and VEGFR3 isonly activated byVEGF-C and -D Upon specific VEGF bind-ing the three VEGF receptors induce receptor dimerizationand autophosphorylation leading to downstream signalingvia a number of secondary messengers including severalprotein kinases and phosphatases that support a proangio-genic phenotype [10ndash12] Important pathways include thephosphoinositide 3-kinaseProtein Kinase BNF-120581B pathwaythat promotes cell survival the mitogen-activated protein

kinase (MAPK) pathway that promotes cell proliferation andthe Rasextracellular signal-regulated kinase (ERK) pathwaythat promotes cell proliferation survival differentiationmigration and angiogenesis Through these signaling path-ways each of the VEGF family provides different actionswith VEGF-A activation of VEGFR2 representing the majormediator of angiogenesis induction [13ndash15]

There are many factors that influence and regulatethe VEGFVEGFR pathway including local environmen-tal hypoxia and various hormones growth factors andcytokines Hormones such as androgens upregulate stromalcell and malignant cell VEGF production and angiogenesisenhancing prostate cancer growth [16ndash18] As such hormonewithdrawal has been shown to inhibit VEGF expression

Prostate Cancer 3

as well as angiogenesis in prostate cancer patients whileinducing apoptosis in these cells [19] Growth factors suchas PDGFs TGF-1205731 and IGFs also have a significant impacton the VEGFVEGFR pathway by inducing the transcriptionand secretion of VEGF [18 20 21] Cytokines such as TNF-120572 IL-6 and IL-8 have also been shown to induce VEGFsignalling to promote angiogenesis and tumourogenesis [2223] IL-6 and IL-8 are also involvedwith the PI3KAktNF-120581Bpathways as well as the MAPK pathway of VEGF signalling[24 25]

3 VEGF and Angiogenesis

Angiogenesis is the growth and development of new bloodvessels and is necessary to supply nutrients and main-tain homeostasis in the tissues of the body [12] Normalangiogenesis is tightly regulated by inducers and inhibitorsof endothelial growth and is established from preexistingvessels which develop ordered and predictable vasculature[26] The actions of VEGF affect numerous cell types thusenabling a multifaceted response Initial activation of VEGFpromotes the secretion of proteolytic enzymes to degradethe basement membrane and extracellular matrix whilst alsoaiding in the proliferation and migration of endothelial cellsto form immature vasculature [13 26] VEGF also maintainsnewly formed vessels by inducing the expression of Bcl-2 andA1 anti-apoptotic proteins that promote cell survival whilstactivating colony formation by attracting mature subsets ofgranulocyte macrophage progenitor cells [27 28] VEGF-A exhibits vast up-regulation under hypoxic conditionswhereby hypoxia-inducible factors (HIFs) stabilize and bindto specific promoter elements present in the promoter regionof VEGF-A [11] VEGFR1 and VEGFR2 are also directlyregulated by HIFs [11]

In cancer alterations in this balance of inducers andinhibitors in favour of angiogenesis can stimulate an ldquoangio-genic switchrdquo via overexpresson of pro-angiogenic factorssuch as VEGF by tumour cells and tumour-associated stroma[26 29] Hypoxic conditions activate the uptake of VEGF andother growth factors and induce the growth of neovascula-ture allowing the tumour cells to gain access to oxygen andnutrients [26 29ndash31] Indeed the induction of angiogenesishas been shown to correlate with the invasive properties oftumours and is associated with poor prognosis [32] Alongwith tumour vascularization activation of genes governingthe disruption of cell to cell adhesion and cell motility enablesproliferation of primary tumour cells as well as allowingdetached cells to disseminate throughout the circulatorysystem [28] In benign prostate glands VEGF expressionis mainly confined to the basal cell layer and has weaklevels of VEGF binding while in prostate tumours VEGF isupregulated and foundbeyond this layer including neoplasticsecretory cells [33]

4 VEGF and Skeletal Metastasis

During the normal development of long bones and vertebraeor bone repair growth and remodeling of bone formationoccurs through osteogenesis [34] A balanced state is created

through the continuous and integrated processes of boneformation and deposition by osteoblasts and bone andmineralized matrix resorption by proteolytic enzymes andhydrochloric acid secreted by osteoclasts derived from thehaematopoietic stem cells of the bone marrow [35 36] It isa complex process dictated by growth factors and cytokinesincluding fibroblast growth factors (FGFs) platelet-derivedgrowth factor (PDGF) transforming growth factor-120573 (TGF-120573) and bone morphogenetic proteins (BMPs) [34] VEGFis expressed by osteoblasts and has autocrine and paracrineeffects including chemotactic migration proliferation anddifferentiation of osteoblasts as well as stimulating theformation survival and resorptive activity of osteoclasts Itis essential for normal angiogenesis and appropriate bonerepair and mineralization in response to bone injury [37]In vivo absence of VEGF leads to impaired blood vesselinvasion cartilage remodeling and skeletal growth [38ndash40] Blood vessels serve as a way of transporting circulat-ing osteoblasts [41] and osteoclast precursors [42] to sitesundergoing active remodelling [43] Cancer metastases tobone cause alterations in normal bone metabolism and thebalance between osteoclasts and osteoblasts in favour of oneor the other resulting in destructive lytic or sclerotic lesionsor a combination of both [44] Osteoclasts are primarilyresponsible for tumour induced bone destruction and duringthe resorption of the bone matrix embedded growth factorsare released that produce a permissive microenvironmentand further promote tumour growth [30 45] Of note inhuman prostate cancer bone metastases generally favour anosteoblastic phenotype in contrast to other metastases suchas those from renal cell carcinoma which are often lytic[46 47]

The spread of prostate cancer metastasis to bone is acomplex process involving tumour cell migration from theprimary tumour site dissemination through the vascularsystem extravasation and finally establishment growth andinvasion at the secondary bone site [4] In a clinical trialof patients with metastatic prostate cancer bone metastaseswere noted in 889 of patients compared with soft tis-suelymph node metastases in 222 and visceral metastasesin 167 demonstrating the preferential homing capabilitiesof prostate metastasis to bone [48] however the propensityof prostate cancer to metastasize to bone and the vertebralcolumn remains largely unknown Prior to the attachment ofthese cancer cells to bone it is thought that a premetastaticnichemay be created by nonmalignant bonemarrow-derivedcells that are stimulated by tumour-secreted proteins whichin combination with various bone-enriched growth factorscytokines proteases and components of the extracellularmatrix such as a high extracellular calcium concentrationsupport the colonization and growth of prostate cancer cellsin bone [49ndash51] The actions of VEGF are thought to assistin tumour cell recognition of bone and encourage nestingof the tumour cells in bone [52] Prior to attachment VEGFvia VEGFR2 modulates the migratory responses of tumourcells encouraging adhesion molecules such as fibronectinand bone sialoprotein within the extracellular matrix [53]Additionally VEGF and its cognate receptors may be ableto regulate integrin activity promoting recognition of the

4 Prostate Cancer

bone matrix [32] Various tumour-expressed growth fac-tors endothelial markers and cytokines attract and activateosteoclasts which in turn disrupt the bone balance throughoverstimulation and discharge of bone-derived growth fac-tors (Figure 2) Other factors which affect the progression ofprostate cancer to bone are Dickkopf-1 (DKK-1) sclerostinand Wnt signalling Upregulation of DKK-1 and sclerostinenhances osteoclastic activity by suppressing Wnt signalingand is thought to be able to inhibit the advancement ofbone cancer metastases [54 55] Whilst DKK-1 levels inpatients with bone metastases decrease Wnt levels rise [56]This increase of Wnt signalling promotes osteoblast andinhibits osteoclast differentiation leading to an osteoblastictumour phenotype [56 57] Furthermore in response tovarious hormonal cellular and cytokine signals receptoractivator of nuclear factor-k B ligand (RANKL) inducesosteoclast formation and activation [58 59] Osteoprotegerin(OPG) may act as a decoy receptor for RANKL in order toinhibit osteoclastogenesis which in turn increases osteoblastformation [60] This RANKRANKLOPG axis therefore isimportant in determining the phenotype of the bone tumour[59] These factors are deposited into the bone matrix andcreate a microenvironment that is favourable for cancer cellsleading to further proliferation of tumour cells and bonedegradation through the secretion of osteolytic factors [61]

Expression levels of VEGF and VEGFRs have also beenshown to be elevated at the site of bone metastases incomparison to primary prostate tumours indicating thatVEGF is an important factor in metastasis developmentparticularly to bone [53] Increased VEGF plasma levels havebeen shown to correlate with skeletal metastasis and poorprognosis in prostate cancer patients and VEGF expressionlevels inmany cancer types have been shown to correlate withpoorer prognosis and metastatic potential [62] Howeverother studies have shown that there is no correlation betweenVEGF serum levels and prognosis [63 64] The expressionof VEGF is upregulated in prostate cancer and is associatedwith clinical stage Gleason score tumour stage progressionmetastasis and survival [65ndash67] In prostate cancer VEGF-dependant autocrine stimulation activates the 120572V1205733 integrinvia the VEGFR2 receptor leading to cell proliferation sur-vival and recognition of extracellular matrix componentswhich may influence their metastatic capabilities [53] Manyprostate cancer cell lines known to produce osteoblasticmetastases highly express VEGF [68]

Interactions of VEGF with markers such as TNF-120572 IL-6 IL-8 and CCN3 have been linked to the pro-angiogenicactivities of tumour cells [69ndash71] High expression of VEGFhas been observed in human metastatic prostate cancer celllines PC-3 Du145 and line LNCaP-C4ndash2 where it has beenshown to promote osteoblastic differentiation and activity invitro [53 71ndash73]

5 Current Treatment of Prostate Cancer andVEGFVEGF-R Targeted Therapies

Traditionally androgen ablation has been themain treatmentfor the prevention of metastases from prostate cancer As

prostate cancer cells are initially dependant on androgenssuppressing the levels of testosterone anddihydrotestosteronedecreases the growth rate of prostate cancer cells [74] How-ever after this initial response these cells can become castrate-resistant and develop a more aggressive phenotype withincreased VEGF expression and proliferative potential [7475]The commonest conventional treatments for bonemetas-tases secondary to prostate cancer are chemotherapy radia-tion and surgery Although chemo- and radiotherapy has thepotential ability to kill rapidly dividing cancer cells they eachhave their own toxic side effects and there is little survivalbenefit in patients with metastatic cancer [76 77] Bisphos-phonates such as zoledronic acid or Denosumab a humanmonoclonal antibody that targets RANKL signalling alsohave a therapeutic role in preventing skeletal-related eventsin bonemetastases via inhibition of osteoclast-mediated boneresorption [78] Patient morbidity and mortality due to localtumour recurrence multimetastatic disease loss of structuralfunction of the bony skeleton destroyed by tumour andmetastatic epidural nerve or spinal cord compression remainimportant challenges

Due to the multifaceted effect VEGF has on tumourangiogenesis tumour cell proliferation and bone destruc-tion antiangiogenic therapies targeting the VEGF path-ways have shown promising early clinical application andare being investigated in clinical trials These anti-VEGFtherapies consist of VEGF-neutralizing antibodies and tyro-sine kinase receptor inhibitors Bevacizumab is a mono-clonal IgG1 antibody that blocks the binding of VEGF-A to its receptors by neutralizing all VEGF isoforms andbioactive proteolytic fragments through the binding of theantibody Fab-ligand epitope to the Gly88 residue of VEGF[79] Bevacizumab is currently in Phase II clinical trialsin relapsed prostate cancer and is approved by the USFood and Drug Administration (FDA) for treatment ofmetastatic colorectal renal and breast cancer and othersolid tumours [80 81] Similarly Aflibercept is anotherantibody which neutralizes VEGF and is currently beingused in Phase II clinical trials for patients with recurrent ormetastatic urothelial cancer [82] Tyrosine kinase inhibitorsact on VEGF receptors inhibiting activation following ligandbinding [83] Ramucirumab is a human IgG1 monoclonalantibody which binds to the extracellular domain of VEGFR-2 and blocks the VEGF-A to VEGFR-2 interaction andsubsequent downstream signaling [84]Other smallmoleculetyrosine kinase receptor inhibitors include Semaxanib whichtargets a single receptor (VEGFR2) and Sorafenib whichtargets multiple tyrosine kinase receptors VEGFR1 -2 and-3 as well as platelet-derived growth factor receptor-120573 [8385] Recently studies have suggested that using anti-VEGFtherapies such as Bevacizumab in concert with radiationtherapy or chemotherapy may be able to increase theresponse to radiation therapy [86] These synergistic actionshave been reported in several preclinical studies and havebeen shown to improve the survival rates in patients withadvanced cancers and decrease levels of radiation necrosis[86ndash88]

Prostate Cancer 5

(2) Angiogenesis

(4) Dissemination

Osteoblasts

Osteoclasts

Tumour cells

Tumour induced bone destruction

Skeletal metastasis

Primary prostate tumour

Effects on cells

Vessel growth and oxygenation of tumour

Molecular effectsgrowth factors

integrin activityPreparation of

premetastatic niche in bone

(1) Proliferationantiapoptosis

(5) Survival

(6) Extravasation

(7) Colonisation

(3) IntravasationVEGF-A

VEGF ET-1 PDGF BMPs

VEGF TNF-120572 ILs PTHrP

TGF-120573 FGFs IGFs

Hypoxiaangiogenic switch

proliferationsurvivaldifferentiationmigrationangiogenesis

Figure 2 Tumour induced bone destruction In the prostate an angiogenic switch promotes the secretion of VEGF leading to variouseffects on cells increasing the release of growth factors and activating integrin activity (1) Proliferationantiapoptosis the cells undergo atransformation that increases the proliferation survival differentiation and migration of the tumour cells (2) Angiogenesis the actions ofVEGF activate angiogenesismdashallowing the tumour cells to access nutrients (3) Intravasation cells invade into the local stroma and thenenter the local vasculature (4) Dissemination cancer cells travel to distant target organs (5) Survival Cells can undergo apoptosis or stopproliferation after dissemination and need to evade local immune surveillance (6) Extravasation invasion of target organ (7) Colonisationafter surviving dissemination and extravasation of the target site tumour cells invade the bone and undergo progressive growth Inmetastaticbone disease tumour cells secrete humoral factors that stimulate osteoclastic and osteoblastic recruitment and differentiation Once theseosteoclasts begin to break down bone growth factors are released stimulating growth of the tumour cells This encourages the tumour cellsto release factors that further increase bone resorption by osteoclast and stimulate bone formation through the activation of osteoblasts

6 Conclusion

To date there have been many articles published suggestingthe possible molecular mechanisms behind the propen-sity of prostate cancer to metastasize to bone and thevertebral column VEGF has been implicated in many ofthese including facilitating cancer cell migration to boneinduction of angiogenesis and stimulating bone formingand resorbing cells of the bone marrow Anti-angiogenictreatments targeting the VEGFVEGF receptor pathway haveshown promising early clinical application Further researchis required to determine whether this may be translated intobetter disease control decreased morbidity higher survivalrates and improved quality of life in patients with prostatecancer

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This work was supported by the National Health andMedicalResearch Council of Australia (Fellowship no 558418) theAustin Health Medical Research Foundation and the Victo-rian Orthopaedic Research Trust

References

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[2] S C Gupta J H Kim S Prasad and B B Aggarwal ldquoReg-ulation of survival proliferation invasion angiogenesis andmetastasis of tumor cells through modulation of inflammatorypathways by nutraceuticalsrdquoCancer andMetastasis Reviews vol29 no 3 pp 405ndash434 2010

[3] K Pietras and A Ostman ldquoHallmarks of cancer interactionswith the tumor stromardquo Experimental Cell Research vol 316 no8 pp 1324ndash1331 2010

6 Prostate Cancer

[4] I Roato P DrsquoAmelio E Gorassini et al ldquoOsteoclasts are activein bone forming metastases of prostate cancer patientsrdquo PLoSONE vol 3 no 11 Article ID e3627 2008

[5] S A Meyer H Singh and A L Jenkins ldquoSurgical treatment ofmetastatic spinal tumorsrdquoMount Sinai Journal of Medicine vol77 no 1 pp 124ndash129 2010

[6] E J Brown and E Chow ldquoBone biomarkers in researchand clinical practicerdquo in Bone Metastases vol 12 of CancerMetastasismdashBiology and Treatment pp 93ndash116 2009

[7] M E McGee-Lawrence and J J Westendorf ldquoHistone deacety-lases in skeletal development and bone mass maintenancerdquoGene vol 474 no 1-2 pp 1ndash11 2011

[8] R L Clifford K Deacon and A J Knox ldquoNovel regulation ofvascular endothelial growth factor-A (VEGF-A) by transform-ing growth factor 1205731 requirement for Smads 120573-catenin andGSK3120573rdquo Journal of Biological Chemistry vol 283 no 51 pp35337ndash35353 2008

[9] F Fan J S Wey M F McCarty et al ldquoExpression and functionof vascular endothelial growth factor receptor-1 on humancolorectal cancer cellsrdquoOncogene vol 24 no 16 pp 2647ndash26532005

[10] A K Olsson A Dimberg J Kreuger et al ldquoVEGF receptorsignallingmdashin control of vascular functionrdquo Nature ReviewsMolecular Cell Biology vol 7 no 5 pp 359ndash371 2006

[11] N Ferrara H-P Gerber and J LeCouter ldquoThe biology of VEGFand its receptorsrdquo Nature Medicine vol 9 no 6 pp 669ndash6762003

[12] H Takahashi andM Shibuya ldquoThe vascular endothelial growthfactor (VEGF)VEGF receptor system and its role under physi-ological and pathological conditionsrdquo Clinical Science vol 109no 3 pp 227ndash241 2005

[13] T L Phung K Ziv D Dabydeen et al ldquoPathological angio-genesis is induced by sustained Akt signaling and inhibited byrapamycinrdquo Cancer Cell vol 10 no 2 pp 159ndash170 2006

[14] J D Hood R Frausto W B Kiosses M A Schwartz and D ACheresh ldquoDifferential 120572v integrin-mediated Ras-ERK signalingduring two pathways of angiogenesisrdquo Journal of Cell Biologyvol 162 no 5 pp 933ndash943 2003

[15] X Jin J Yin S-H Kim et al ldquoEGFR-AKT-Smad signalingpromotes formation of glioma stem-like cells and tumor angio-genesis by ID3-driven cytokine inductionrdquo Cancer Researchvol 71 no 22 pp 7125ndash7134 2011

[16] A C Levine X-H Liu P D Greenberg et al ldquoAndrogensinduce the expression of vascular endothelial growth factor inhuman fetal prostatic fibroblastsrdquo Endocrinology vol 139 no 11pp 4672ndash4678 1998

[17] MW Jackson ldquoA potential autocrine role for vascular endothe-lial growth factor in prostate cancerrdquo Cancer Research vol 62pp 854ndash859 2002

[18] X Li Y Feng J Liu et al ldquoEpigallocatechin-3-gallate inhibitsIGF-I-stimulated lung cancer angiogenesis through down-regulation of HIF-1alpha and VEGF expressionrdquo Journal ofNutrigenetics and Nutrigenomics vol 6 no 3 pp 169ndash178 2013

[19] R K Jain N Safabakhsh A Sckell et al ldquoEndothelial celldeath angiogenesis andmicrovascular function after castrationin an androgen-dependent tumor role of vascular endothelialgrowth factorrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 95 no 18 pp 10820ndash108251998

[20] J Yu C Ustach and H-R C Kim ldquoPlatelet-derived growthfactor signaling and human cancerrdquo Journal of Biochemistry andMolecular Biology vol 36 no 1 pp 49ndash59 2003

[21] K Eisermann C J Broderick A Bazarov et al ldquoAndrogenup-regulates vascular endothelial growth factor expression inprostate cancer cells via an Sp1 binding siterdquoMolecular Cancervol 12 p 7 2013

[22] T Cohen D Nahari L W Cerem G Neufeld and B-Z LevinldquoInterleukin 6 induces the expression of vascular endothelialgrowth factorrdquo Journal of Biological Chemistry vol 271 no 2pp 736ndash741 1996

[23] Z Von Marschall T Cramer M Hocker G Finkenzeller BWiedenmann and S Rosewicz ldquoDual mechanism of vascularendothelial growth factor upregulation by hypoxia in humanhepatocellular carcinomardquo Gut vol 48 no 1 pp 87ndash96 2001

[24] B Paule S Terry L Kheuang P Soyeux F Vacherot and Ade Taille ldquoThe NF-120581BIL-6 pathway in metastatic androgen-independent prostate cancer new therapeutic approachesrdquoWorld Journal of Urology vol 25 no 5 pp 477ndash489 2007

[25] F Luppi A M Longo W I de Boer K F Rabe and P SHiemstra ldquoInterleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptortransactivationrdquo Lung Cancer vol 56 no 1 pp 25ndash33 2007

[26] B I Terman and K V Stoletov ldquoVEGF and tumor angiogene-sisrdquoThe Einstein Quarterly Journal of Biology andMedicine vol18 no 2 2001

[27] S P Ivy J Y Wick and B M Kaufman ldquoAn overview ofsmall-molecule inhibitors of VEGFR signalingrdquoNature ReviewsClinical Oncology vol 6 no 10 pp 569ndash579 2009

[28] P G Tsoutsou and M L Koukourakis ldquoAngiogenesis andbone metastasis implications for diagnosis prevention andtreatmentrdquo in Bone Metastases vol 12 of Cancer MetastasismdashBiology and Treatment pp 51ndash76 2009

[29] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[30] G Van Der Pluijm B Sijmons H Vloedgraven M DeckersS Papapoulos and C Lowik ldquoMonitoring metastatic behaviorof human tumor cells in mice with species-specific polymerasechain reaction elevated expression of angiogenesis and boneresorption stimulators by breast cancer in bone metastasesrdquoJournal of Bone and Mineral Research vol 16 no 6 pp 1077ndash1091 2001

[31] R A Cairns I S Harris and T W Mak ldquoRegulation of cancercell metabolismrdquo Nature Reviews Cancer vol 11 no 2 pp 85ndash95 2011

[32] S De J Chen N V Narizhneva et al ldquoMolecular pathway forcancer metastasis to bonerdquo Journal of Biological Chemistry vol278 no 40 pp 39044ndash39050 2003

[33] J Kollermann and B Helpap ldquoExpression of vascular endothe-lial growth factor (VEGF) and VEGF receptor Flk-1 in benignpremalignant andmalignant prostate tissuerdquoAmerican Journalof Clinical Pathology vol 116 no 1 pp 115ndash121 2001

[34] V J Mandracchia S C Nelson and E A Barp ldquoCurrentconcepts of bone healingrdquo Clinics in Podiatric Medicine andSurgery vol 18 no 1 pp 55ndash77 2001

[35] B F Boyce E Rosenberg A E de Papp et al ldquoThe osteoclastbone remodelling and treatment of metabolic bone diseaserdquoEuropean Journal of Clinical Investigation vol 42 no 12 pp1332ndash1341 2012

[36] J Street and B Lenehan ldquoVascular endothelial growth factorregulates osteoblast survivalmdashevidence for an autocrine feed-back mechanismrdquo Journal of Orthopaedic Surgery and Researchvol 4 no 1 article 19 2009

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Prostate Cancer 7

[38] H-P Gerber K J Hillan A M Ryan et al ldquoVEGF is requiredfor growth and survival in neonatal micerdquo Development vol126 no 6 pp 1149ndash1159 1999

[39] H-P Gerber V Dixit and N Ferrara ldquoVascular endothelialgrowth factor induces expression of the antiapoptotic proteinsBcl-2 and A1 in vascular endothelial cellsrdquo Journal of BiologicalChemistry vol 273 no 21 pp 13313ndash13316 1998

[40] H-P Gerber T H Vu A M Ryan J Kowalski Z Werb andN Ferrara ldquoVEGF couples hypertrophic cartilage remodelingossification and angiogenesis during endochondral bone for-mationrdquo Nature Medicine vol 5 no 6 pp 623ndash628 1999

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[43] M Kassem L Risteli LMosekilde FMelsen and E F EriksenldquoFormation of osteoblast-like cells from human mononuclearbone marrow culturesrdquo Acta Pathologica Microbiologica etImmunologica Scandinavica vol 99 no 3 pp 269ndash274 1991

[44] J-K Jin F Dayyani and G E Gallick ldquoSteps in prostate cancerprogression that lead to bone metastasisrdquo International Journalof Cancer vol 128 no 11 pp 2545ndash2561 2011

[45] K N Weilbaecher T A Guise and L K McCauley ldquoCancer tobone a fatal attractionrdquo Nature Reviews Cancer vol 11 no 6pp 411ndash425 2011

[46] DCossigny andGMYQuan ldquoIn vivo animalmodels of spinalmetastasisrdquoCancer andMetastasis Reviews vol 31 no 1 pp 99ndash108 2012

[47] P Curtin H Youm and E Salih ldquoThree-dimensional cancer-bonemetastasismodel using ex-vivo co-cultures of live calvarialbones and cancer cellsrdquo Biomaterials vol 33 no 4 pp 1065ndash1078 2012

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[50] C Zhang M Soori F L Miles et al ldquoParacrine factorsproduced by bone marrow stromal cells induce apoptosisand neuroendocrine differentiation in prostate cancer cellsrdquoProstate vol 71 no 2 pp 157ndash167 2011

[51] R R Langley and I J Fidler ldquoThe seed and soil hypothesisrevisitedmdashthe role of tumor-stroma interactions in metastasisto different organsrdquo International Journal of Cancer vol 128 no11 pp 2527ndash2535 2011

[52] J A Sterling J R Edwards T J Martin and G R MundyldquoAdvances in the biology of bone metastasis how the skeletonaffects tumor behaviorrdquo Bone vol 48 no 1 pp 6ndash15 2011

[53] J Chen S De J Brainard and T V Byzova ldquoMetastaticproperties of prostate cancer cells are controlled by VEGFrdquo CellCommunication and Adhesion vol 11 no 1 pp 1ndash11 2004

[54] M P Yavropoulou AH van Lierop N AHamdy et al ldquoSerumsclerostin levels in Pagetrsquos disease and prostate cancer with bonemetastases with awide range of bone turnoverrdquoBone vol 51 no1 pp 153ndash157 2012

[55] D Diarra M Stolina K Polzer et al ldquoDickkopf-1 is a masterregulator of joint remodelingrdquo Nature Medicine vol 13 no 2pp 156ndash163 2007

[56] J L Sottnik C L Hall J Zhang et al ldquoWnt andWnt inhibitorsin bone metastasisrdquo BoneKEy Reports vol 1 p 101 2012

[57] S M Tu A Som B Tu et al ldquoEffect of Pagetrsquos disease of bone(osteitis deformans) on the progression of prostate cancer bonemetastasisrdquoBritish Journal of Cancer vol 107 no 4 pp 646ndash6512012

[58] Y Li D Kong A Ahmad B Bao and F H Sarkar ldquoTargetingbone remodeling by isoflavone and 331015840-diindolylmethane inthe context of prostate cancer bone metastasisrdquo PLoS ONE vol7 no 3 Article ID e33011 2012

[59] D L Lacey W J Boyle W S Simonet et al ldquoBench to bedsideelucidation of theOPG-RANK-RANKL pathway and the devel-opment of denosumabrdquo Nature Reviews Drug Discovery vol 11no 5 pp 401ndash419 2012

[60] L Mercatali M Ricci E Scarpi et al ldquoRANKRANK-LOPGin patients with bone metastases treated with anticancer agentsand zoledronic acid a prospective studyrdquo International Journalof Molecular Sciences vol 14 no 6 pp 10683ndash10693 2013

[61] T A Guise K S Mohammad G Clines et al ldquoBasic mecha-nisms responsible for osteolytic and osteoblastic bone metas-tasesrdquo Clinical Cancer Research vol 12 no 20 pp 6213sndash6216s2006

[62] J L F Duque K R Loughlin R M Adam P W KantoffD Zurakowski and M R Freeman ldquoPlasma levels of vascu-lar endothelial growth factor are increased in patients withmetastatic prostate cancerrdquo Urology vol 54 no 3 pp 523ndash5271999

[63] P J Saylor K R Kozak M R Smith et al ldquoChanges inbiomarkers of inflammation and angiogenesis during androgendeprivation therapy for prostate cancerrdquo Oncologist vol 17 no2 pp 212ndash219 2012

[64] F Botelho F Pina P Silva G Figueiredo F Cruz andN Lunet ldquoVascular endothelial growth factor (VEGF) andprostate pathologyrdquo International Brazilian Journal of Urologyvol 36 no 4 pp 430ndash438 2010

[65] E K Amankwah T A Sellers and J Y Park ldquoGene variants inthe angiogenesis pathway and prostate cancerrdquo Carcinogenesisvol 33 no 7 pp 1259ndash1269 2012

[66] M Borre SM Bentzen BNerstroslashm and JOvergaard ldquoTumorcell proliferation and survival in patients with prostate cancerfollowed expectantlyrdquo Journal of Urology vol 159 no 5 pp1609ndash1614 1998

[67] T T Tomia H Gustavsson W Wang K Jennbacken KWelen and J-EDamber ldquoCastration resistant prostate cancer isassociatedwith increased blood vessel stabilization and elevatedlevels of VEGF and Ang-2rdquo Prostate vol 72 no 7 pp 705ndash7122012

[68] N K Thudi C K Martin M V P Nadella et al ldquoZoledronicacid decreased osteolysis but not bone metastasis in a nudemouse model of canine prostate cancer with mixed bonelesionsrdquo Prostate vol 68 no 10 pp 1116ndash1125 2008

[69] G Ligresti A C Aplin P Zorzi A Morishita and R FNicosia ldquoMacrophage-derived tumor necrosis factor-120572 is anearly component of themolecular cascade leading to angiogene-sis in response to aortic injuryrdquoArteriosclerosisThrombosis andVascular Biology vol 31 no 5 pp 1151ndash1159 2011

[70] C Fischbach J K Hyun S X Hsiong M B Evangelista WYuen and D J Mooney ldquoCancer cell angiogenic capability isregulated by 3D culture and integrin engagementrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 106 no 2 pp 399ndash404 2009

8 Prostate Cancer

[71] V Ouellet and P M Siegel ldquoCCN3 modulates bone turnoverand is a novel regulator of skeletal metastasisrdquo Journal of CellCommunication and Signaling vol 6 no 2 pp 73ndash85 2012

[72] Y Takei K Kadomatsu Y Yuzawa S Matsuo and T Mura-matsu ldquoA small interfering RNA targeting vascular endothelialgrowth factor as cancer therapeuticsrdquo Cancer Research vol 64no 10 pp 3365ndash3370 2004

[73] S Srinivasan R Kumar S Koduru A Chandramouli and CDamodaran ldquoInhibiting TNF-mediated signaling a novel ther-apeutic paradigm for androgen independent prostate cancerrdquoApoptosis vol 15 no 2 pp 153ndash161 2010

[74] E Corey ldquoAndrogen suppression the good the bad and theuglyrdquo Andrology vol 1 Article ID e106 2012

[75] L Pan S Baek P R Edmonds et al ldquoVascular endothelialgrowth factor (VEGF) expression in locally advanced prostatecancer secondary analysis of radiation therapy oncology group(RTOG) 8610rdquo Radiation Oncology vol 8 article 100 2013

[76] L Yang S You V Kumar et al ldquoIn vitro the behaviors ofmetastasis with suppression of VEGF in human bonemetastaticLNCaP-derivative C4-2B prostate cancer cell linerdquo Journal ofExperimental amp Clinical Cancer Research vol 31 article 402012

[77] T Brabletz D Lyden P S Steeg et al ldquoRoadblocks to transla-tional advances on metastasis researchrdquo Nature Medicine vol19 no 9 pp 1104ndash1109 2013

[78] N Kamiya H Suzuki T Endo et al ldquoAdditive effect ofzoledronic acid on serum prostate-specific antigen changes forhormone-sensitive prostate cancer patients with bone metas-tasis treated by combined androgen blockaderdquo InternationalJournal of Urology vol 19 no 2 pp 169ndash173 2012

[79] A F Dawood P Lotfi S N Dash S K Kona K T Nguyenand M I Romero-Ortega ldquoVEGF release in multiluminalhydrogels directs angiogenesis from adult vasculature in vitrordquoCardiovascular Engineering and Technology vol 2 no 3 pp173ndash185 2011

[80] V T Labropoulou A DTheocharis A Symeonidis S S Skan-dalis N K Karamanos and H P Kalofonos ldquoPathophysiologyand pharmacological targeting of tumor-induced bone diseasecurrent status and emerging therapeutic interventionsrdquoCurrentMedicinal Chemistry vol 18 no 11 pp 1584ndash1598 2011

[81] K N Syrigos E Karapanagiotou P Boura CManegold andKHarrington ldquoBevacizumab-induced hypertension pathogene-sis and managementrdquo BioDrugs vol 25 no 3 pp 159ndash169 2011

[82] P Twardowski W M Stadler P Frankel et al ldquoPhase IIstudy of aflibercept (VEGF-Trap) in patients with recurrent ormetastatic urothelial cancer a California cancer consortiumtrialrdquo Urology vol 76 pp 923ndash926 2010

[83] SMWilhelm L Adnane P Newell A Villanueva J M LlovetandM Lynch ldquoPreclinical overview of sorafenib a multikinaseinhibitor that targets both Raf and VEGF and PDGF receptortyrosine kinase signalingrdquo Molecular Cancer Therapeutics vol7 no 10 pp 3129ndash3140 2008

[84] A Grothey and E Galanis ldquoTargeting angiogenesis progresswith anti-VEGF treatment with large moleculesrdquo NatureReviews Clinical Oncology vol 6 no 9 pp 507ndash518 2009

[85] A OrsquoDonnell A Padhani C Hayes et al ldquoA Phase I study of theangiogenesis inhibitor SU5416 (semaxanib) in solid tumoursincorporating dynamic contrast MR pharmacodynamic endpointsrdquo British Journal of Cancer vol 93 no 8 pp 876ndash8832005

[86] A Narayana D Gruber S Kunnakkat et al ldquoA clinical trialof bevacizumab temozolomide and radiation for newly diag-nosed glioblastoma clinical articlerdquo Journal of Neurosurgeryvol 116 no 2 pp 341ndash345 2012

[87] H I Hurwitz N C Tebbutt F Kabbinavar et al ldquoEfficacy andsafety of bevacizumab in metastatic colorectal cancer pooledanalysis from seven randomized controlled trialsrdquo Oncologistvol 18 no 9 pp 1004ndash1012 2013

[88] M Furuse N Nonoguchi S Kawabata et al ldquoBevacizumabtreatment for symptomatic radiation necrosis diagnosed byamino acid PETrdquo Japanese Journal of Clinical Oncology vol 43no 3 pp 337ndash341 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Prostate Cancer

Endothelial cell VEGF

VEGF-AVEGF-B (VEGF-C

VEGF-D)

VEGF-CVEGF-D

VEGFR1

NRP-2VEGFR1 and-2

NRP-1VEGFR2 VEGFR2 and-3

HSPGVEGFR3

PI3K

AktPKBp38MAPK

Ras

MAK

ERK

Cell survival

Cell proliferation

VEGF-AVEGF-A

VEGFR2

VEGF-CVEGF-D

NF-120581B

Cell proliferationsurvivaldifferentiationmigration andangiogenesis

Figure 1 VEGF receptor bindingThefivemammalian vascular endothelial growth factors (VEGF-A-D) bind to the receptor tyrosine kinasesVEGF receptor (VEGFR1-3 and co-receptors HSPG NRP-1 and NRP-2) VEGFR-binding leads to the formation of homodimers andorheterodimers Proteolytic cleavage enables VEGF-C and -D to bind VEGFR-2 forming a homodimer The binding and activation of VEGFR-2 lead to downstream signaling of the PI3K MAPK and Ras pathways which promote cell survival proliferation differentiation migrationand angiogenesis

immunoglobulin-like folds [10] Additionally heparin sul-phate proteoglycans (HSPGs) as well as neuropilins (NRP-1and NRP-2) can act as coreceptors for VEGF and promoteVEGFR activation [11 12] Each VEGF family member bindswith differential affinity for their receptors for exampleVEGFR2 is primarily activated by VEGF-A and VEGFR3 isonly activated byVEGF-C and -D Upon specific VEGF bind-ing the three VEGF receptors induce receptor dimerizationand autophosphorylation leading to downstream signalingvia a number of secondary messengers including severalprotein kinases and phosphatases that support a proangio-genic phenotype [10ndash12] Important pathways include thephosphoinositide 3-kinaseProtein Kinase BNF-120581B pathwaythat promotes cell survival the mitogen-activated protein

kinase (MAPK) pathway that promotes cell proliferation andthe Rasextracellular signal-regulated kinase (ERK) pathwaythat promotes cell proliferation survival differentiationmigration and angiogenesis Through these signaling path-ways each of the VEGF family provides different actionswith VEGF-A activation of VEGFR2 representing the majormediator of angiogenesis induction [13ndash15]

There are many factors that influence and regulatethe VEGFVEGFR pathway including local environmen-tal hypoxia and various hormones growth factors andcytokines Hormones such as androgens upregulate stromalcell and malignant cell VEGF production and angiogenesisenhancing prostate cancer growth [16ndash18] As such hormonewithdrawal has been shown to inhibit VEGF expression

Prostate Cancer 3









4 Prostate Cancer








Prostate Cancer 5

(2) Angiogenesis

(4) Dissemination

Osteoblasts

Osteoclasts

Tumour cells


Skeletal metastasis


Effects on cells






(5) Survival

(6) Extravasation

(7) Colonisation


VEGF ET-1 PDGF BMPs






6 Conclusion




Acknowledgments


References




6 Prostate Cancer



































Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Prostate Cancer 3









4 Prostate Cancer








Prostate Cancer 5

(2) Angiogenesis

(4) Dissemination

Osteoblasts

Osteoclasts

Tumour cells


Skeletal metastasis


Effects on cells






(5) Survival

(6) Extravasation

(7) Colonisation


VEGF ET-1 PDGF BMPs






6 Conclusion




Acknowledgments


References




6 Prostate Cancer



































Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 Prostate Cancer








Prostate Cancer 5

(2) Angiogenesis

(4) Dissemination

Osteoblasts

Osteoclasts

Tumour cells


Skeletal metastasis


Effects on cells






(5) Survival

(6) Extravasation

(7) Colonisation


VEGF ET-1 PDGF BMPs






6 Conclusion




Acknowledgments


References




6 Prostate Cancer



































Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Prostate Cancer 5

(2) Angiogenesis

(4) Dissemination

Osteoblasts

Osteoclasts

Tumour cells


Skeletal metastasis


Effects on cells






(5) Survival

(6) Extravasation

(7) Colonisation


VEGF ET-1 PDGF BMPs






6 Conclusion




Acknowledgments


References




6 Prostate Cancer



































Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















6 Prostate Cancer



































Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Prostate Cancer 7


































8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















8 Prostate Cancer
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the role of vascular endothelial growth...

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