Targeting the tumor microenvironment: focus on angiogenesis.

Abstract

Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

Full text

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Hindawi Publishing Corporation
Journal of Oncology
Volume 2012, Article ID 281261, 16 pages
doi:10.1155/2012/281261
Review Article
Targeting theTumorMicroenvironment:FocusonAngiogenesis
FengjuanFan,AlexanderSchimming, DirkJaeger, andKlausPodar
MedicalOncology,NationalCenterforTumorDiseases(NCT),UniversityofHeidelbergandGermanCancerResearchCenter(DKFZ),
Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
Correspondence should be addressed to Klaus Podar, klaus.podar@med.uni-heidelberg.de
Received 1 May 2011; Accepted 23 June 2011
Academic Editor: Kalpna Gupta
Copyright © 2012 Fengjuan Fan et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also
selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment
is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established.
Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has
led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib,
temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors
(colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the
interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and
summarize derived targeted therapies.
1.Introduction
Cancer research in both solid and hematologic malignancies
until recently predominantly focused on the identification
of genetic changes which are intimately associated with the
induction and progression of tumors and metastasis [1].
A variety of multistep tumor models with accumulating
somatic mutations has been proposed [2], most prominently
the multistep colon cancer model of Dr. Vogelstein’s group
[3, 4]. In addition to focal genetic lesions (point mutations),
chromosomal aberrations (e.g., aneuploidy, translocations,
chromosomal deletions) as well as epigenetic alterations
(e.g., DNA methylation, histone deacetylation, nucleosome
remodeling, and RNA-associated silencing) induce deregu-
lated expression of oncogenes and suppressor genes thereby
leading to tumor cell proliferation, transformation and
invasion [5, 6]. Recent studies add yet another facet to the
complexmultistepmodeloftumorigenesisbydemonstrating
that tumor cells carrying genomic and epigenomic abnor-
malities also trigger changes in their microenvironment.
In turn, these changes enable the formation of a selective
supportive “tumor microenvironment” [7, 8].
The cellular tumor microenvironment that is, the bone
marrow microenviroment is composed of nonhematopoietic
cells including endothelial cells (ECs); cancer-associated
fibroblasts (CAFs); and cells involved in bone homeostasis
includingchondroblasts,osteoclasts,
and hematopoietic cells including immune cells (including
natural killer cells (NK) cells, tumor-associated macrophages
(TAMs), T lymphocytes, monocytes); erythrocytes; megak-
aryocytes and platelets; stem cells; progenitor and precursor
cells;andcirculating endothelial
Thenoncellularmicroenvironment
the extracellular matrix (ECM) proteins including fi-
bronectin, laminin, collagen, osteopontin, proteoglycans,
and glycosaminoglycans—and the liquid milieu (cytokines
and growth factors, proteases) (Table 1). Tumor cell-
induced disruption of the microenvironment homeostasis
between the highly organized cellular and extracellular
compartments support sustained proliferative signaling,
evade growth suppressors, resist cell death, enable replicative
immortality, activate invasion and metastasis, reprogram
energy metabolism, evade immune destruction, and induce
drug resistance and angiogenesis. Based on our enhanced
understanding of the functional importance of the tumor
microenvironment and tumor angiogenesis, in particular,
new molecular targets have been identified.
andosteoblasts;
precursors
is
(CEPs).
composedof

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2Journal of Oncology
Table 1: Tumor microenvironment and its compartments.
Tumor entities
Microenvironment
Epithelial solid tumors
For example, Breast Cancer
fibronectin, laminin, collagen, proteoglycans,
thrombospondin, fibrinogen, elastin, fibrin,
tenascin, tetranectin
Hematological tumors
For example, multiple myeloma
Extracellular matrix (ECM)
fibronectin, laminin, collagen, proteoglycans,
glycosaminoglycans
Cellular
Hematopoietic: TAM, T and B lymphocytes,
neutrophils, NK cells, mesenchymal stem cells
Hematopoietic: HSCs, BM-derived CEPs,
hematopoietic and mesenchymal progenitor
and precursor cells, NK cells, NKT cells,
macrophages, T and B lymphocytes, DCs,
monocytes, platelets, megakaryocytes,
erythrocytes
nonhematopoietic: fibroblasts/BMSCs,
chondrocytes, OCs, OBs, ECs
nonhematopoietic: CAFS, myoepithelial cells,
ECs, pericytes
Hormones: estrogen, progesterone
Liquid
cytokines and growth factors: VEGF, HGF/SF,
bFGF, PDGFα/β, TGFα/β, IL-1, IL-6, TNFα,
GM-CSF, CSF-1, IGF-1/2, EGF, SDF-1
Cytokines and growth factors: VEGF, IGFs,
TNFα, CD40, IL-1, IL-6, IL-10, IL-11, IL-15,
IL-21, HGF, bFGF, SDF-1, TGFβ, LIF, OSM,
MIP-1α, Wnts
proteases: uPA, plasmin, MMPs (e.g.,
MMP-2, -9)
proteases: cathepsin B and D, elastase, uPA,
plasmin, MMPs (e.g., MMP-1, -2, -3, -9)
TAM: tumor-associated macrophage; NK: nature killer; CAFS: cancer-associated fibroblasts; EC: endothelial cell; HSC: hematopoietic stem cells; CEP:
circulating endothelial precursor; NKT: nature killer T; DC: dendritic cell; BMSC: bone marrow stromal cell; OC: osteoclast; OB: osteoblast; VEGF: vascular
endothelial growth factor; HGF/SF: hepatocyte growth factor/scatter factor; bFGF: basic Fibroblast Growth Factors; PDGF: platelet-derived growth factor;
TGF: transforming growth factor; TNF: tumor necrosis factor; IL: interleukin; GM-CSF: granulocyte macrophage colony stimulating factor; CSF: colony
stimulating factor; EGF: epidermal growth factor; SDF: stromal cell-derived factor; uPA: urokinase plasminogen activator; MMP: matrix metalloproteinase;
IGF: Insulin-like growth factor; LIF: leukaemia inhibitory factor; OSM: oncostatin M; MIP-1α: macrophage inflammatory protein 1α.
References for breast cancer: [8–11].
References for multiple myeloma: [12].
This paper aims to illustrate important aspects in
the interrelationship between tumor cells and the tumor
microenvironment, tumor angiogenesis in particular, in
tumor progression. Four tumor entities, in which antian-
giogenic agents have already significantly changed treatment
strategies, are taken as examples: colorectal cancer (CRC),
renal cell carcinoma (RCC), and breast cancer (BC), as well
as multiple myeloma (MM).
2.Tumor Angiogenesis
Research on tumor angiogenesis is a major focus in
biomedicine. Historically, Dr. Virchow was the first to iden-
tify a huge number of blood vessels in tumors in 1863 [13].
Few decades later in 1907, Goldman was the first to describe
tumor vascularization in carcinomas of the stomach, the
liver, and other organs [14]. In 1913, Murphy reported about
the angiogenic response induced by Jensen rat sarcoma cells
in the chick chorioallantoic membrane (CAM) [15]. The
term “angiogenesis” was first used in 1935 and described
the formation of new blood vessels in the placenta [16] and
four years later in wound healing and tumor growth [17].
However, it was not until 1971 when Folkman hypothesized
that inhibition of angiogenesis may be a potential way to
inhibit cancer progression [18]. Subsequently, independent
studies by Senger and Dvorak, Ferrara and Henzel, as
well as Connolly and colleagues led to the purification,
identification and cloning of vascular endothelial growth
factor (VEGF), the key proangiogenic factor [19–23]. Since
then, our knowledge of molecular mechanisms to tumor
angiogenesiscontinuallyincreasedleadingtothediscoveryof
promising antiangiogenic therapies for tumor patients [24,
25]. Specifically, the impact of the tumor microenvironment,
and tumor angiogenesis in particular, has been studied in
greater detail in three types of solid cancer (CRC, RCC,
BC)—andMM.Thesediseasesserveasparadigmdiseasesfor
ongoing studies also in other tumor entities.
During tumorigenesis, the appropriate balance between
proangiogenic and antiangiogenic molecules which arise
from cancer cells and stromal cells in response to direct cell-
cell, cell-ECM binding as well as to autocrine and paracrine
growth factor stimulation, is lost [26, 27]. The “angiogenic
switch”, a rapid increase of blood vessel formation to support
tumor growth, is triggered by (1) oncogene-mediated tumor
expression of angiogenic proteins including VEGF, fibroblast
growth factor (FGF), platelet derived growth factor (PDGF),
endothelial growth factor (EGF), lysophosphatic acid (LPA),
and angiopoietin (Ang), (2) metabolic and/or mechanical
stress, (3) genetic mutations, (4) the immune response, and
maybe most prominently (5) hypoxia. Tumor-angiogenesis
therefore depends on tumor type, site, growth, and stage
of disease and contributes to tumor growth, invasion, and
metastasis.

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Journal of Oncology3
The main mechanism of tumor angiogenesis is endothe-
lial sprouting which crucially depends on VEGF upregu-
lation and the interaction between ECs, pericytes, stroma
cells as well as their association with the ECM [28, 29].
Specifically, VEGF and angiopoietin activate matrix degrad-
ing enzymes including the plasminogen activator (PA) and
matrix metalloproteinases (MMPs) to loosen the matrix and
favor EC migration [30]. VEGF and angiopoietin-2 (Ang-
2)/type I tyrosine kinase receptor 2 (TIE 2) system then
induce the detachment of pericytes and thereby increase
vessel porosity. Plasma proteins are exuded and provide a
gradient for EC migration [31–34]. Mechanistically, vessel
sprouting is mediated by specialized ECs: tip cells lead the
new sprout; stalk cells trail behind the pioneering tip cell,
proliferate to form an elongating, stalk and create a lumen;
and endothelial nonproliferating phalanx cells sense and
regulate perfusion in the persistent sprout. Functionally,
VEGF induces both NOTCH 1-mediated proliferation in
stalk cells as well as directed migration of delta-like 4 (DLL
4)-expressing tip cells towards the sources of angiogenic
factors. Endothelial cell-derived factor epidermal growth
factor-like domain multiple 7 (Egfl 7) and components
of the ECM then regulate vascular lumen formation [35].
Finally, PDGF produced by ECs then recruits pericytes,
which surround and stabilize new vessels.
Besides sprouting, the formation of the endothelial
lining of tumor vessels is promoted by cooption of
neighboring preexisting vessels [36], intussusception (inser-
tion of connective tissue columns into vessel lumen), glom-
eruloid angiogenesis, as well as VEGF-induced recruitment
of highly proliferative circulating endothelial cells (CECs)
and endothelial progenitor cells (EPCs) from the BM,
hematopoietic stem cells (HSCs), progenitor cells, mono-
cytes, and macrophages [37]. In addition, tumor cells
themselves act as ECs to form functional avascular blood
conduits or mosaic blood vessels [38–42].
Oxygen tension is the key regulator of VEGF expression,
predominantly via the hypoxia-inducible factor (HIF)/von
Hippel-Lindau tumor suppressor gene (VHL) pathway.
Under normoxic conditions, prolyl hydroxylase domain
(PHD) proteins hydroxylate prolyl residues on HIF, which
are recognized by VHL, polyubiquitinated, and undergo
proteasomal degradation. Tumor growth is often accompa-
nied by a decrease in oxygen tension due to insufficient
vascularization [43]. In turn, the process of tumor angio-
genesis gets initiated and blood vessels supply nutrients and
oxygen for the tumors that reach a hypoxic and necrotic
area [43]. Under hypoxic conditions, PHD proteins are
inactive,andnonhydroxylatedHIFaccumulates,translocates
to the nucleus and binds to hypoxia-response elements
(HRE) thereby initiating transcription of various genes that
play a central part in angiogenesis. Genes induced by HIF
include VEGF, PDGF, transforming growth factor-β (TGF-
β),TGFα,epidermalgrowthfactorreceptor(EGFR),insulin-
like growth factor 2 (IGF2), MMP1, stromal cell-derived
factor 1 (SDF1), glucose transporter 1 (involved in glucose
metabolism), as well as carbonic anhydrase 9 (CAIX), and
activin B [44–47]. Factor inhibiting HIF (FIH) modulates
interaction of HIF with the coactivators CBP/p300 [48].
HIF is also regulated by oxygen-independent pathways
via growth-factor receptors or other signaling molecules.
Specifically, growth factors, signaling molecules, and loss
of function mutations of molecules such as VHL, p53,
and PTEN, trigger HIF-1α synthesis. HIF expression is also
controlled by specific microRNAs. A recent study identified
a unique microRNA in hypoxic endothelia cells, miR424,
that promotes HIF-1 stabilization and angiogenesis [49, 50].
Importantly, besides being a key regulator of angiogenesis,
HIF activity is required for tumor cell survival and pro-
liferation, migration, invasion, pH regulation, metabolism,
drug and radiation resistance, immune evasion, and genetic
stability [51, 52].
3.Colorectal Cancer
Major improvements in the therapy of CRC have been
made during the last decades. These improvements are
based on our increased knowledge of the role of the
tumor microenvironment, and angiogenesis in particular,
in CRC tumorigenesis. In the late 1980s, Dr. Vogelstein
postulated a paradigm of multistep carcinogenesis in CRC
involving a progressive series of specific and well-defined
genetic alterations in tumor suppressor genes (APC, p53,
or DCC) and in oncogenes (K-Ras), which render normal
mucosa to carcinoma [53, 54]. Besides inducing tumor cell
proliferation, survival, migration, and drug resistance, these
alterations trigger changes in the tumor microenvironment,
tumor angiogenesis in particular, via upregulation of VEGF
as well as deregulation of other molecules including EGFR
and COX2. Increased levels of VEGF and EGFR expression
have been found in patients with localized as well as
metastatic CRC [55–60]. Based on successful clinical phase
III trials both VEGF inhibitors (e.g., bevacizumab) as well as
EGFR inhibitors (e.g., cetuximab, panitumumab) have been
approved and incorporated into novel treatment regimens of
progressed CRC.
Metabolic products of cyclooxygenase 2 (COX2), pros-
taglandins in particular, contribute to neovascularisation
and support vasculature-dependent growth of CRC, inva-
sion, and metastasis [31, 61, 62]. COX2 is upregulated in
approximately 50% of adenomas and 85% of adenocarci-
nomas [63, 64] and associated with worse survival among
CRC patients [65]. Genetic deletion of COX2 dramatically
reducesintestinalpolypformationsupportingakeyfunction
of COX2 in CRC tumorigenesis [66]. Functionally, COX2
triggers secretion of MMP2 and MMP9 and enhances the
expression of proangiogenic growth factors including VEGF
and bFGF. It therefore contributes to the dissolution of the
collagen matrix, EC migration, and formation of tubular
networks [67–70]. COX2 inhibitors suppress VEGF and
bFGF expression and thereby block angiogenesis [71–73].
Indeed, both aspirin and nonaspirin-NSAIDs given daily
reduce the incidence of CRC significantly [74, 75].
Another potential therapeutic target is endoglin, a
membrane-steady TGFβ coreceptor regulating tumorangio-
genesis in CRC [76, 77]. High levels of soluble Endoglin have
beenfoundinCRCandBCpatients[78]whereitcontributes
to EC dysfunction [79, 80]. However, exact mechanism

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4 Journal of Oncology
of soluble endoglin on tumor angiogenesis remain to be
identified.
In summary, inhibitors of growth factors contributing to
tumor angiogenesis such as VEGF, EGF, and also COX2 have
alreadybeenincorporatedintonoveltreatmentregimensand
maintenance therapies in CRC. Promising future therapeutic
targets include endoglin.
4.Renal CellCarcinoma
Renal cell carcinoma/hypernephrom accounts for 2-3% of
all cancer cases in adults. It is the seventh most common
cancer in men and the ninth most common in women
[81]. While localized RCC has a 5-year survival rate of
60–70%, metastatic RCC is the most lethal of all uro-
logical cancers [82]. Resistant to chemotherapy [81], only
immunotherapy with IL-2 and interferon α (IFN α) has been
utilized for systemic RCC therapy until most recently [83].
The introduction of antiangiogenic agents has dramatically
improved treatment options in metastatic RCC. Indeed, an
unprecedented six antiangiogenic agentshave been approved
forRCCtreatmentduringthelast5yearsincludingsunitinib,
temsirolimus, everolimus, pazopanib, bevacizumab, and
sorafenib. These agents improve progression-free survival.
However, improvements of overall survival have not been
demonstrated yet.
The evaluation of antiangiogenic agents for treatment
of RCC has been triggered by the finding that RCC is
a highly vascular tumor and that increased microvessel
density (MVD) correlates with increased risk of metastasis,
recurrence and adverse prognosis. High expression of VEGF
and other angiogenic factors are predominantly triggered by
the inactivation of the VHL tumor suppressor gene due to
the loss of 3p [84–88]. Consequently, HIF is not degraded
even under normoxic conditions [85]. Furthermore, VHL
has many functions that are independent of HIF [89]. For
example, inactivated VHL cannot interact with fibronectin
and hydroxylated collagen IV. It thereby leads to impaired
ECM organization invasion and angiogenesis in RCC [90,
91].
Besides VHL/HIF signaling, other signaling pathways
may also participate in the regulation of secreted angiogenic
factors in RCC. For example, in VHL-defective RCC cells,
oncoprotein HDM2 not only affects constitutively expressed
HIFα, but also directly regulates protein levels of HIF
angiogenic targets (e.g., VEGF, PA inhibitor-1 (PAI-1), and
endothelin-1 (ET-1)) [92].
RCC is one of the most immunogenic tumors [93].
Importantly, besides its effects on angiogenesis VEGF mod-
ulates immune tolerance in the tumor microenvironment by
attenuating dendritic cell differentiation [94], and increasing
secretion of immunosuppressive cytokines [95]. Anti-RCC
activity of VEGF-inhibitors may therefore, at least in part,
alsobemediatedviamodulationoftheantitumorimmunity.
5.Breast Cancer
In 2010, BC was the cancer with the most new cases
(207,090 women) of females in the USA and forth highest
death rate (39,840 women) [96]. As in CRC and RCC,
VEGF expression is also upregulated in BC. Moreover,
angiogenesis represents a major independent prognostic
factor in BC [97]. VEGF production and secretion within
the BC microenvironment is triggered by a number of
stimuli including growth factors, cytokines, hormones, loss
of p53 function, RAS and SRC mutations, hypoxia as well
as overexpression of HER2 (HER2/neu, ErbB2) [98–100].
Moreover, high levels of MMP-9 are produced and secreted
by BC cells [101] and release sequestered VEGF from the
adjacent ECM [102]. Importantly, VEGF levels are higher
in premenopausal patients than in postmenopausal patients
indicating that steroid hormones increase VEGF expression
[103]. Indeed, upregulation of VEGF in tumor cell lines is
triggered by the interaction of the ERα/estradiol-complex
with an imperfect estrogen response element located 1.5kb
upstream of the VEGF transcription start site [104, 105].
HER2 is a member of the EGFR family encoded by the
ERB2 gene. In human BC, the HER2 gene is amplified in 20–
30% of all BC [106, 107]. Phosphorylation of the tyrosine
kinase domain results in tumor cell and EC proliferation and
survival via PI3K- and Ras/MEK/MAPK-signaling pathways
[57, 108, 109]. In addition to phosphorylation, cleavage of
the extracellular domain of HER2 generates an intracellular
domain (p95) which activates these signaling pathways.
Another regulator of angiogenesis in BC is osteoprote-
gerin (OPG), a glycoprotein belonging to the TNF receptor
(TNFR) superfamily whose production is triggered by direct
cell-EC contact [110]. High levels of OPG are present in
tumor ECs and correlate with tumor grade in BC [111].
Similarly, the transcription factor HOXB9 is overex-
pressed in 42% of patients with BC. It induces production
of TGF-β, ErbB ligands, and several angiogenic factors
(VEGF, bFGF, IL-8, and ANGPTL-2) thereby resulting in
the induction of mesenchymal cell fate, invasion, as well as
angiogenesis [112].
Finally, fes proto-oncogene (also known as fps) which
encodes a Src homology 2 (SH2) domain-containing cyto-
plasmic PTK mediates tumor angiogenesis and metastasis
[113]. Indeed the tumor microenvironment in Fes-deficient
miceshowedreducedvascularityandfewertumor-associated
macrophages indicating a therapeutic role for fes-inhibition
[114].
In addition to bevacizumab, a variety of additional
antiangiogenic agents is under clinical investigation for
treatment of BC in the palliative as well as in the adjuvant
setting. Importantly, also the anti-BC activity of tamoxifen
is, at least in part, due to its antiangiogenic effect [115–117].
6.Multiple Myeloma
MM is a B-cell neoplasm characterized by excess clonal
proliferation of malignant plasma cells in the bone marrow,
elevated serum and urine monoclonal protein, osteolytic
bone lesions, renal disease, and immunodeficiency. MM is
the second most frequent malignancy of the blood in the
USA. It causes about 1% of neoplastic diseases and 13%
of hematological malignancies [118, 119]. The development
of MM involves both early and late genetic changes in the

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Journal of Oncology5
tumor cell as well as selective supportive conditions by the
bone marrow (BM) microenvironment, BM angiogenesis in
particular [120]. It is suggested that MGUS and nonactive
MM in which the tumor growth is arrested are “avascular
phases” of plasma cell tumors, while the active MM is the
“vascular phase”, which is associated with clonal expansion
and epigenetic modifications of the microenvironment as
wellasthe“angiogenicswitch”[121,122].Importantly,these
findings correlate with disease progression and poor prog-
nosis. Moreover, BM MVD at the time of initial diagnosis is
an important prognostic factor for median overall survival
(OS) and median progression-free survival (PFS) in patients
undergoing autologous transplantation as frontline therapy
for MM [123].
VEGF within the MM BM microenvironment induces
growth, survival as well as migration of MM cells in an
autocrine manner via VEGFR-1 and triggers angiogenesis
via VEGF-2 in ECs [122–127]. Recent studies suggest the
existence of MM-specific ECs (MMECs) which produce
growthandinvasivefactorsforplasmacells,includingVEGF,
FGF-2, MMP-2 as well as MMP-9. Compared to healthy
human umbilical vein EC (HUVEC), MMECs secrete higher
amounts of the CXC chemokines (e.g., IL8, SDF1-α, MCP-
1), which act in a paracrine manner to mediate plasma cell
proliferation and chemotaxis [120–123, 126, 128, 129]. In
turn, MM cells and stromal cells prolong survival of ECs
both by increased secretion of EC survival factors, such as
VEGF, and by decreased secretion of antiangiogenic factors
[123, 130, 131].
Based on the enhanced understanding of the functional
importance of the MM BM microenvironment and its
interrelation with the MM cell resulting in homing, seeding,
proliferation and survival, new molecular targets have been
identified and derived treatment regimens in MM have
already changed fundamentally during recent years. The
anti-MM activity of thalidomide, bortezomib, and lenalido-
mide is mediated, at least in part, also via antiangiogenic
effects[132].ForthetreatmentofMM,additionalantiangio-
genic therapies are therefore being evaluated in combination
with conventional or novel anti-MM therapies [12, 127].
7.Inhibitorsof Angiogenesis(Table 2)
7.1. Thalidomide and the IMiDs (Lenalidomide/Revlimid,
Pomalidomide/Actimid). In 1994, D’Amato et al. studied the
mechanism of thalidomide’s teratogenicity and found that
thalidomide(Celgene)isapotentialinhibitorofangiogenesis
[133]. Based on this finding and the discovery that bone
marrow MVD plays a key role in MM pathogenesis, thalido-
mide was used empirically to treat patients with refractory
relapsed MM in the late 90s. Remarkable clinical responses
rendered thalidomide to be the first antiangiogenic agent for
cancer treatment [134]. Currently, thalidomide is not only
used in patients with refractory/relapsed but also with newly
diagnosed MM.
Subsequently, a series of thalidomide-derived immun-
omodulatory drugs (IMiDs) including lenalidomide (Rev-
limid) and pomalidomide (Actimid) have been developed
[135]. A phase I dose-escalation trial using lenalidomide
in patients with relapsed and refractory MM demonstrated
either response or stabilization of disease in 79% cases
[136]. Two clinical phase II trials confirmed these data
and achieved complete responses with favorable side effect
profiles; two clinical phase III trials comparing lenalidomide
to dexamethasone/lenalidomide treatment of relapsed MM
provided the basic for its FDA approval in 2006. In the
relapsed/refractory setting an overall response of 30% was
achieved by the new IMID pomalidomide, alone or in
combination with dexamethasone. More than 100 clinical
studies with thalidomide or lenalidomide combined with
other agents are currently recruiting or ongoing.
AdversesideeffectsofthalidomideandtheIMiDsinclude
polyneuropathy, fatigue, skin rash, and venous thromboem-
bolism (VTE), or blood clots, which could lead to stroke
or myocardial infarction. Both thalidomide and the IMiDs
overcome the growth and survival advantage conferred by
theBMmilieu,atleastinpartbydownregulatingVEGF[137,
138], and inhibition of proliferation and capillarogenesis of
MMECs [128].
7.2. Bevacizumab (Avastin). Bevacizumab (Genetech) [139]
binds biologically active forms of VEGF and prevents its
interaction with VEGF receptors (VEGFR-1 and VEGFR-
2), thereby inhibiting endothelial cell proliferation and
angiogenesis. In preclinical studies bevacizumab reduced
microvascular growth and inhibited metastasis of colon
growth in nude mice [140–142].
When tested in patients with metastatic CRC beva-
cizumab in combination with conventional chemotherapy
demonstrated significant survival benefits. Based on this
finding, the US FDA approved bevacizumab in February
2004, followed by the EMEA approval in January 2005,
as first-line treatment of metastatic CRC in combination
with 5-fluorouracil-(FU-) based chemotherapy regimens.
In 2006, bevacizumab in combination with 5-FU was also
approved for second-line treatment of CRC. In contrast,
the use of bevacizumab in the adjuvant setting cannot be
recommended [143–145]. Bevacizumab is therefore the first
VEGF-targeting agent approved both by the US FDA as well
as the EMEA for cancer treatment [146].
Since its initial approval as first-line treatment in
metastatic CRC in 2004, bevacizumab has been approved for
use in combination with other chemotherapeutics in four
other tumor types: in 2009 (US) and 2007 (EU) for advanced
RCC, in 2008 for metastatic HER2-negative BC, in 2009 for
glioblastoma, and in 2004 for non-small cell lung cancer
(NSCLC) [147–150].
Specifically, the E2100 study was the first Phase III
study using bevacizumab in metastatic BC as first-line treat-
ment. Bevacizumab was investigated in combination with
and without paclitaxel. In combination with bevacizumab,
progression-free survival was doubled (5.8 months to 11.3
months). The overall response rate increased from 22 to
50%. Because of this study, bevacizumab was approved for
metastatic BC [151]. But as the overall survival did not
show any benefit, Fojo and Wilkerson [152] believe that the
E2100 trial overestimated the benefit of bevacizumab and

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6Journal of Oncology
Table 2: Summary of drugs, their revealed targets and indications in clinical trails. Drugs without a single treatment trial are marked with a
“∗”.
Drug (brand name,
company)
TargetApproved
Clinical trials with
single treatment
Indication
Bevacizumab (Avastin,
Genentech/Roche)
Monoclonal antibody
against VEGFA
mCRC, mRCC, NSCLC,
metastatic HER2-negative
breast cancer,
glioblastoma
Phase I, II
Multiple solid tumors (e.g., RCC,
BC, pancreatic, prostate, ovarian,
brain cancers) and hematologic
malignancies (e.g., MM)
Sunitinib, SU11248
(Sutent, Pfizer)
TKI of VEGFR 1–3,
PDGFRα/β, c-Kit, Flt3,
RET, CSF-1R
TKI of VEGFR 1–3,
PDGFRα/β, c-kit
tyrosine kinases
TKI of Multiple cell
surface kinases (VEGFR
1–3, RET, PDGFRβ,
Flt-3, c-Kit, CSF-1) and
intracellular kinases
(CRAF, BRAF, mutant
BRAF)
TKI of VEGFR, EGFR
and RET
mRCC, GIST Phase I
Multiple solid tumors (e.g., RCC,
BC, melanoma, lung)
Pazopanib (Votrient,
GlaxoSmithKline)
mRCCPhase I, II
Multiple solid tumors (e.g., BC,
RCC, ovarian, lung) and others
(e.g., lymphoma)
Sorafenib, BAY43-9006
(Nexavar, Bayer)
mRCC, unresectable
hepatocellular carcinoma
Phase I, II
Multiple solid tumors (e.g., RCC,
BC, melanoma, lung cancers)
and hematologic malignancies
(e.g., MM)
Vandetanib, ZD6474
(Zactima, AstraZeneca)
Bortezomib, PS-341
(Velcade, Millennium
Pharmaceuticals)
Metastatic medullary
thyroid cancer
Phase I, IINSCLC, RCC, glioblastoma
26S proteasome
inhibitor
MM, relapsed mantle cell
lymphoma
Phase I, II
MM, lymphoma, leukemia and
multiple solid tumors (e.g., RCC,
BC, lung, prostate)
Multiple solid tumors (e.g., RCC,
BC, melanoma, prostate, liver
cancers) and hematologic
malignancies (e.g., lymphoma)
Multiple solid tumors (e.g., BC,
pancreatic, gastric cancers) and
lymphoma
Temsirolimus (Torisel,
Wyeth)
mTOR inhibitor mRCCPhase I, II
Everolimus, RAD001
(Afinitor, Novartis)
mTOR inhibitor
Advanced renal cell
carcinoma
Phase I, II
Thalidomide (Thalomid,
Celgene)
Angiogenesis inhibitor,
multiple
MM
∗
MM
Lenalidomide, CC-5013
(Revlimid, Celgene)
Angiogenesis inhibitor,
Thalidomide derivative
MMPhase I, II
MM, lymphoma, chronic
lymphocytic leukemia, and
multiple solid tumors (e.g., CRC,
ovarian)
Pomalidomide, CC-4047
(Actimid, Celgene)
Aflibercept, VEGF-trap
(ZALTRAP,
Sanofi-Aventis and
Regeneron)
Angiogenesis inhibitor,
Thalidomide derivative
No yet approvedPhase I MM, Lymphoma
Decoy receptor for all
VEGF-A isoforms
No yet approved
∗
mCRC, RCC, Ovarian, NSCLC,
prostate cancers, lymphoma,
leukemia
Axitinib, AG-013736
(Pfizer)
TKI of VEGFR 1–3,
PDGFRβ, c-KIT and
CSF-1
No yet approved Phase I
mRCC, BC, NSCLC, metastatic
pancreatic cancer, GIST, lung
cancer, thyroid cancer
Advanced solid tumors, (e.g.,
CRC, BC, carcinoma of urinary
tract)
CRC, BC, mRCC, Advanced
liver, gastric, prostate, ovarian,
and NSCL cancers, melanoma
Multiple solid tumors (e.g., CRC,
glioblastoma, NSCLCs) and
hematologic malignancies (e.g.,
leukemia)
Icrucumab, IMC-18F1
(ImClone)
Monoclonal antibody
against VEGFR-1
No yet approvedPhase I
Ramucirumab,
IMC-1121b (ImClone)
Monoclonal antibody
against VEGFR-2
No yet approved
∗
Vatalanib, PTK787
(Novartis)
TKI of VEGFR 1–3,
PDGFRα/β, and c-KIT
Not yet approved
∗

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Journal of Oncology7
Table 2: Continued.
Drug (brand name,
company)
TargetApproved
Clinical trials with
single treatment
Indication
Enzastaurin,
LY317615.HCl (Eli Lilly)PKC inhibitor
Not yet approved
∗
BC, mCRC, Brain tumor,
advanced NSCL, glioblastoma,
lymphoma
RCC, CRC, BC, ovarian, prostate
cancer, lung, brain, head and
neck cancers, glioblastoma,
melanoma
mCRC, pancreatic, HNSCC,
NSCLC, lung
Cediranib, AZD2171
(Recentin, AstraZeneca)
TKI of VEGFR 1–3Not yet approvedPhase I
Vectibix, panitumumab
(Amgen)
Erbitux, cetuximab,
(Imclone, Bristol-Myers
Squibb)
Trastuzumab, herceptin
(Genentech)
Tykerb, lapatinib
(GlaxoSmithKline)
Tamoxifen, Novadex,
Istubal, Valodex
(AstraZeneca)
EGFR mCRCPhase I, II
EGFRmCRCPhase I, II
mCRC, HSNCC, brain, MM,
lung, pancreatic, liver
HER2 receptor
Gastric cancer, HER2
positive BC
Phase I, IIBC, gastric
EGFR and HER2
receptor
BC Phase I, II
BC, CRC, lung, HNSCC,
pancreatic, melanoma
Estrogen receptorBC Phase I, IIBC, bladder, melanoma, prostate
TKI: tyrosine kinase inhibitors; mCRC: metastatic colorectal cancer; NSCLC: nonsmall cell lung cancer; mRCC: metastatic renal cell carcinoma; GIST:
gastrointestinal stroma tumor after progression; MM: multiple myeloma; BC: breast cancer; HNSCC: head and neck sequmous cell carcinoma.
that further studies need to target the VEGF polymorphism
of VEGF in order to identify the patients that derive true
benefit from bevacizumab [153]. Based on two double-blind
studies (AVADO and RIBBON-1) showing high toxicity
without significant improvements of progression-free sur-
vival [154–156], the use of bevacizumab as first-line therapy
in progressed Her2-negative BC has been removed by the
US FDA in 2010. In a meta-analysis, Ranpura et al. report
that addition of bevacizumab to systemic antineoplastic
therapy is associated with a significantly increased risk
(relative risk of 1.46; incidence, 2.5% versus 1.7%) of fatal
adverse events (FAEs), in BC patients [157, 158]. However,
clinical studies evaluating bevacizumab in combination with
conventional therapies both in Her2-negative and also Her2-
positive patients are ongoing. It may be possible to focus
bevacizumabtreatmentinpatientsmostlikelytobenefit,and
avoid treatment of patients unlikely to benefit or more likely
to experience toxic effects [157].
Although generally well tolerated, side effects of beva-
cizumab treatment include minor (hypertension, protein-
uria, nosebleed, upper respiratory infection, gastrointestinal
symptoms, and headache) and rarely serious (gastrointesti-
nal perforations, hemorrhage, and thrombolysis) adverse
effects.
7.3. Cetuximab (Erbitux). Cetuximab (Merck, ImClone,
Briston-Myers-Squibb) is a recombinant, human-IgG1/
mouse chimeric monoclonal antibody which blocks phos-
phorylation and activation of receptor-associated kinases
by binding to the receptor. Erbitux is single-used or
used in combination with other therapies to treat CRC.
The US FDA used three separate clinical trials as a base
to approve Erbitux for treatment of EGFR-expressing,
recurrent metastatic CRC in patients who are intolerant
to irinotecan-based chemotherapy in 2004. In 2007, the
US FDA expanded labeling and granted regular approval
for single-agent cetuximab for the treatment of patients
with EGFR-expressing metastatic CRC after failure of both
irinotecan- and oxaliplatin-based chemotherapy regimens
(http://www.cancer.gov/).
Known side-effects are rash, asthenia/malaise, diarrhea,
nausea, abdominal pain, vomiting, fever, and infusion reac-
tion [159–162].
7.4. Panitumumab (Vectibix). Panitumumab (Amgen), a
recombinant, human IgG2 kappa monoclonal antibody,
binds specifically to the extracellular domain of EGFR and
thereby prevents its activation and downstream signaling
sequeale [163–166]. In 2006, panitumumab was approved
by the US FDA for treatment of EGFR-expressing metastatic
CRC with disease progression despite prior treatment; in
2008 by the EMEA for the treatment of refractory EGFR-
expressing metastatic CRC in patients with nonmutated K-
Ras.
Known side-effects include dermatological toxicities,
ocular toxicities, hypomagnesemia, fatigue, abdominal pain,
nausea, diarrhea and constipation.
7.5. VEGF-Trap (ZALTRAP, Aflibercept), HuMV833, and
Other Monoclonal Antibodies Targeting VEGF. VEGF-trap
(Sanofi-Aventis and Regeneron) is a soluble decoy receptor
protein consisting of a hybrid Fc construct in which domain
2 of VEGFR-1 is fused to domain 3 of the VEGFR-
2 [167, 168]. VEGF-trap is known to have high affinity

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8 Journal of Oncology
to all isoforms of VEGF-A. It caused vessel-regression
of coopted vessels in a model of neuroblastoma [169].
Several clinical phase II/III trials testing the VEGF-trap
in solid and hematologic malignancies including CRC,
MM, pancreatic cancer, prostate cancer, NSCLC are ongo-
ing (http://clinicaltrials.gov/). On April 26, 2011, Sanofi-
Aventis and Regeneron reported about the positive phase III
results with VEGF-trap in second-line mCRC. The VELOUR
study evaluates ZALTRAP in combination with FOLFIRI
chemotherapy versus FOLFORI plus placebo. Exact results
are eagerly awaited for the second half of 2011.
Similarly,HuMV833,ahumanizedmonoclonalIgGanti-
body-binding VEGF-A isoforms (VEGF121 and VEGF165),
demonstrated antitumor effects in a variety of human tumor
xenograft models [170, 171].
Additionally, antibodies against VEGFR-1 or VEGFR-
2 (IMC-18F1, IMC-1121B, ImClone) are under preclinical
and clinical investigation. IMC-18F1 is a fully human,
high affinity neutralizing antibody that specifically blocks
VEGFR-1 activation, which has demonstrated preclinical
activity in BC [172]. IMC-1121B (ramucirumab), a fully
human monoclonal IgG1 antibody against the extracellular
domainofVEGFR-2,iscurrentlyunderevaluationinvarious
entities including advanced liver, kidney, prostate, ovarian,
colorectal, melanoma, BC, and NSCL cancer [173, 174].
7.6.Trastuzumab(Herceptin). Trastuzumab(Genentech)isa
recombinant humanized monoclonal antibody which binds
totheextracellulardomainoftheHER2receptorandinhibits
theintracellulartyrosinekinaseactivity.Inaddition,itblocks
cleavage of HER2 and thereby the production of p95, inter-
fereswith either homodimerization or heterodimerization of
HER2 with itself or other HER receptors, and recruits Fc-
competent immune effector cells and other components of
antibody-dependent cell-mediated cell cytotoxicity (ADCC).
In 1998, trastuzumab was FDA approved for treatment of
patients with HER2-positive metastatic BC in combination
with paclitaxel. In 2006, FDA approval of trastuzumab was
expanded for the adjuvant setting in combination with
chemotherapy regimens containing doxorubicin, cyclophos-
phamide, and paclitaxel. In January 2008, FDA approval was
revised to include the use of trastuzumab also as a single
agent in the adjuvant setting [175].
7.7. Small Molecule Inhibitors. Although Avastin is an
effective medication and studies testing the VEGF-trap or
VEGFR-targeting antibodies are promising, drug resistance
always develops likely due to targeting a single tumorigenic
pathway. Indeed extended blockade of VEGF alone results in
tumor revascularization, dependent on other proangiogenic
factors such as FGF [176]. Small-molecule inhibitors have
the advantage of being orally available as well as more
promiscuous in target inhibition and also less expensive
[177, 178]. Based on these therapeutic advantages, many
tyrosine kinase inhibitors (TKIs) have been developed and
subjected to clinical trials. Indeed, the second-generation
multi-targeted receptor kinase inhibitors (RTKIs) sorafenib,
sunitinib, and pazopanib have now been approved for the
treatment of advanced RCC and gastrointestinal stroma
tumor (GIST), hepatocellular carcinoma (HCC). Moreover,
preliminary data in other malignancies, most prominently
including CRC and BC are promising.
7.7.1. Sorafenib (Nexavar). Sorafenib (Bayer HealthCare
Pharmaceuticals and Onyx Pharmaceuticals) [179, 180] is
a RTK inhibitor which targets VEGFR2, VEGFR-3, Raf,
PDGFRβ, Flt3, and c-Kit. It was approved for the treatment
of advanced RCC in 2005 and for the treatment of unre-
sectable HCC in 2007. Advanced clinical studies in NSCLC
and melanoma are ongoing.
7.7.2. Sunitinib (Sutent). Sunitinib (Pfizer) is another multi-
targeted TKI which targets VEGFR2, PDGFRα/β, c-Kit, Flt3,
RET [181–184]. Based on a phase III clinical trial, in which
sunitinib demonstrated improvements in progression-free
survival when compared to IFNα, it was approved for first-
line and second-line therapy of metastatic RCC [185, 186].
In addition, sunitinib was also approved for treatment of
GIST in 2006 [187]. Advanced clinical studies are ongoing
in breast, colorectal, and lung cancer. Both sorafenib and
sunitinib alone or in combination therapy are under clinical
evaluation in MM.
7.7.3. Temsirolimus (Torisel) and Everolimus (Afinitor). Tem-
sirolimus (Wyeth Pharmaceuticals), a derivative of rapa-
mycin, is a specific inhibitor of the mammalian target of
rapamycin (mTOR). mTOR pathway has an important role
in regulating the synthesis of HIF and proteins that control
cell proliferation, such as c-myc and cyclin D1. Therefore,
inhibiting mTOR in RCC downregulates HIF activity and
stops the production of cell-cycle regulators [188, 189].
In 2007, Temsirolimus was approved for the treatment
of advanced RCC. As compared with IFNα, temsirolimus
improved overall survival among patients with mRCC and
poor prognosis [190].
Everolimus (Novartis), another rapamycin analogue was
approvedfortreatmentofpatientswithmRCCwhosedisease
had progressed despite prior treatment with sunitinib,
sorafenib, or both in 2009 [191, 192].
Clinical studies which evaluate the activity of tem-
sirolimus and everolimus in other tumor entities including
BC, gastric cancer, HCC, MM, and lymphoma are ongoing.
7.7.4. Pazopanib (Votrient). Pazopanib (GlaxoSmithKline)
is a novel orally available, small-molecule tyrosine kinase
inhibitor of VEGF-receptor-1, -2, -3 with IC50’s of 10, 30,
and 47nM, respectively. In 2010, pazopanib was approved
as the third TKI and the last among the six treatments
for mRCC (sorafenib, sunitinib, temsirolimus, everolimus,
bevacizumab) approved by the FDA during the last 5 years.
The basis for this approval was a randomized, double-blind,
placebo-controlledphaseIIIstudyevaluatingtheefficacyand
safety of pazopanib in 435 patients with locally advanced
and/or mRCC. The median PFS for the pazopanib was 9.2
months compared with 4.2 months for the placebo in overall
population (P < 0.001) [193]. Moreover, the combination of

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Journal of Oncology9
pazopanib with lapatinib was effective in patients with BC,
and preclinical data in MM were promising [194]. Clinical
studies which evaluate the activity of pazopanib in other
tumor entities are ongoing.
7.7.5. Axitinib. Axitinib (Pfizer) is an oral, potent, and
selective inhibitor of VEGFR 1–3, PDGFRβ, and c-KIT.
Promising data from a clinical phase I study [195] prompted
the clinical evaluation of Axitinib in a variety of malignan-
cies. Excitingly, clinical activity has now been demonstrated
in sorafenib-refractory metastatic RCC [196] and patients
with advanced NSCLC [197]. Moreover, a clinical phase
III trial in patients with unresectable, locally advanced, or
metastatic pancreatic cancer treated with gemcitabine plus
axitinib is now ongoing to verify a small gain in overall
survival observed in a clinical phase II trial [198]. Clinical
trials in mCRC showed no benefit of axitinib in first-
and second-line combination therapies with oxaliplatin-
containing chemotherapies in comparison to bevacizumab
[199].
Additional clinical studies are ongoing in GIST, lung
cancer, thyroid cancer, and breast cancer. Dose-limiting
toxicities primarily seen at higher dose levels included
hypertension, hemoptysis, and stomatitis. The observed hy-
pertension was manageable with medication. Stomatitis was
generally tolerable and managed by dose reduction or drug
holidays.
7.7.6. Lapatinib (Tyverb). Lapatinib (GlaxoSmithKline) is
another orally available TKI inhibiting both EGFR and
HER2 receptors [200–202]. It was FDA approved in 2007
for combination therapy for triple-positive BC patients
already treated with capecitabine or which have progressed
on trastuzumab. In 2010, lapatinib additionally received
accelerated approval as front-line therapy in this patient
cohort.
Side effects of Tyverb include diarrhea, palmar-plantar
erythrodysesthesia,nausea,rash,vomiting,muscularinflam-
mation, stomatitis, pain in extremities, dyspnea, and fatigue
[203–206].
8.Discussion
Recent studies delineate a key role for the tumor microenvi-
ronment in tumorigenesis. Investigating the complex func-
tional interrelation between the cellular and noncellular
compartments of the tumor microenvironment has already
led to the identification of new therapeutic targets. One
pivotal compartment within the microenvironment is the
vascular niche. Indeed, 40 years after Dr. Folkman’s seminal
postulation in 1971 that angiogenesis is required for tumor
growth and progression and may therefore represent a new
target for cancer therapy [18], it is well established that
angiogenesis plays an important role in solid as well as
in hematologic malignancies. Tumor angiogenesis is now
recognized to be a hallmark of cancer, initiated by enhanced
tumor/tumor-stroma cell-specific production of proangio-
genic molecules, and/or suppression of antiangiogenic fac-
tors (angiogenic switch) as well as via tumor-associated
hypoxia. The introduction of antiangiogenic agents into
clinical practice was a milestone event in cancer therapy
during the last decade.
VEGF, EGF, and PDGF represent key factors in tumor
angiogenesis. Blocking BM angiogenesis in MM with
thalidomide; and VEGF with the first-in-class antiangio-
genic drug bevacizumab; or EGFR with cetuximab in
CRC have become established anticancer strategies. Follow-
ing the introduction of bevacizumab, efforts focused on
the identification of compounds targeting VEGF signaling
sequelae that can be given orally. Several second-generation
orally available small-molecule antiangiogenic drugs have
now been identified including sunitinib, pazopanib, and
sorafenib and have recently been approved for treatment
of cancers including CRC, BC, RCC, and MM. However
the optimal use of antiangiogenics is tumor- and stage-
dependent. Moreover, although antiangiogenic antibodies as
well as small molecules targeting VEGF and EGF signaling
pathways significantly prolong overall survival of cancer
patients, resistance always develops and disease relapse is
inevitable.Recentmolecularmechanisticstudiesmayexplain
the disappointing results of previous clinical studies using
VEGF inhibitors alone either in early or refractory/progressive
disease. Modest, though significant, survival benefits were
observedinpatientswithadvancedtumorstreatedwithbeva-
cizumaband other antiangiogenics even whencombined with
conventional chemotherapies. Further studies are needed
to increase our understanding of tumor angiogenesis and
of how resistance against antiangiogenic agents develops.
Potential mechanisms of evasive resistance include the
redundancy of proangiogenic signals in later disease stages;
recruitment of vascular progenitor cells and proangiogenic
monocytes from the bone marrow, increased and tight
pericyte coverage, or increased capabilities for invasion and
metastasis; preexisting inflammatory cell-mediated vascular
protection; hypovascularity; invasive and metastatic coop-
tion of normal vessels; and mutational alteration of genes
within endothelial cells [207]. Therapeutic benefits may be
achieved by initiating treatment with VEGF-inhibitors early:
by using antiangiogenic cocktails, which not only target
VEGF both in patients with early and late-stage disease, as
well as metronomic therapy [208].
Novel approaches to improve antiangiogenic therapy
include strategies to target the angiopoietin-TIE system, Hif-
1, endothelial-specific integrin/survival signaling (e.g., by
cilengitide) as well as the use of vascular-disrupting agents
(VDAs), which selectively disrupt already existing tumor
vessels by targeting dysmorphic endothelial cells. Given the
benefits of combination therapy, it is also crucial to optimize
existing or identify new treatment regimens in order to
reduce drug-associated toxic side effects.
In summary, antiangiogenic compounds like thalido-
mide, bevacizumab, sorafenib, sunitinib, and pazopanib,
temsirolimus and everolimus have already demonstrated
activity in a variety of cancers most prominently including
BC, CRC, RCC, and MM. However, with the increase of
our knowledge of the complexity of molecular mechanisms
contributing to tumor angiogenesis in general, and MM
BM angiogenesis in particular, we aim to identify additional

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10Journal of Oncology
therapeutic targets, to further optimize treatment regimens;
and to reduce mechanisms leading to antiangiogenic drug-
resistance in order to further improve patient outcome and
reduce drug toxicity.
Acknowledgment
F. Fan and A. Schimming contributed equally to this paper.
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