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16]

Educational
Forum

Hypertension, cancer and angiogenesis: Relevant

epidemiological and pharmacological aspects
A. Ray, S. Ray*, B. C. Koner**

ABSTRACT
Department of
Pharmacology, Meharry
Medical College,
Nashville, TN 37208,
USA, *Division of
Developmental Biology,
Vanderbilt University
School of Medicine,
Nashville, TN 37232,
USA, and **Department
of Biochemistry, JIPMER,
Pondicherry - 605 006,
India.
Received: 26.4.2004
Revised: 10.7.2004
Accepted: 15.8.2004
Correspondence to:
B. C. Koner
E-mail:
bckoner@hotmail.com

Hypertension and cancer are two leading diseases in the world. Often they coexist in patients.
They share some common predisposing factors e.g., ageing, obesity, alcohol consumption and
smoking habit. Abnormal angiogenesis (i.e. the formation of new blood vessels from an existing
vasculature) is a common pathological feature, and some pro-angiogenic factors e.g., vascular
endothelial growth factor, basic fibroblast growth factor, tumor necrosis factoralpha and few
interleukins are common mediators in both the conditions. Among these, the most important is
vascular endothelial growth factor, a specific mitogen for vascular endothelium. It increases vascular permeability and induces proteolytic enzymes that are necessary for vascular remodeling. Monocyte/macrophages also have been shown to play a role in angiogenesis by releasing some of the
above mediators. Angiogenesis is essential for the growth and metastasis of solid tumors. The
essence of impaired angiogenesis (despite high level of angiogenic factors), probably due to signaling
defects in the endothelium in hypertension, is not clearly understood. Some anticancer drugs e.g.,
taxanes, vinblastine, temozolomide and doxorubicin have antiangiogenic activity. Nevertheless,
several classes of specific antiangiogenic agents are being evaluated for their anticancer effects
and are emerging as new drugs for cancer treatment. COX-2 inhibitors (e.g., celecoxib and rofecoxib),
neovastat, thalidomide analogues and some cytokine inhibitors also inhibit angiogenesis. Although
certain antihypertensives are found to have antiangiogenic properties, some show pro-angiogenic
activity. Also, a number of epidemiological studies have found an association between the use of
antihypertensive drugs and risk of cancer. However, a better understanding of common cell biology and the relationship between hypertension and malignancy may be helpful in elucidating
more preventive and therapeutic avenues to manage hypertension and cancer.
KEY WORDS: Antihypertensive drugs, macrophages, new blood vessel, tumors

Introduction
Hypertension is the most common cardiovascular disease
and a major public health problem in both developed and developing countries.1 Hypertension is a major risk factor for
stroke, coronary heart disease, cardiac failure and renal failure. Prevention and treatment of hypertension have been shown
to reduce morbidity and mortality substantially.2
Epidemiological evidence from prospective studies points
to the possibility that there may be an association between the
pathogenesis of hypertension and cancer.3 Many epidemiological factors and pathophysiological pathways are quite similar
in two distinct disorders. Phaeochromocytoma, a rare tumor of
the adrenal medulla is associated with hypertension. The incidence of both hypertension and cancer increases with the ageing process and interestingly, some other risk factors are common. Obesity is responsible for hypertension and some forms

of cancer. Similarly, alcohol consumption and smoking have a

contributing role in blood pressure elevation and malignancy.
Worldwide, in the year 2000, approximately 56 million
deaths occurred and non-communicable diseases accounted
for 58% of the total number of deaths.4 Cancer accounted for
over 7 million deaths (13% of total mortality and 22% of noncommunicable disease mortality) worldwide in 2000, which
was second to cardiovascular diseases (29% of total). Lung
cancer was the leading cause of cancer deaths in the world,
accounting for 17% of total cancer mortality. Lung cancer was
also the most common cancer in the world in 2000, accounting for 13% of the total cancer incidence, followed by cancers
of the colon and rectum, breast, stomach and liver.4 However,
it is interesting to note that the majority of cancer patients
have coexistent diseases. With more than 50% of the cancer
patients reporting cardiovascular disorders including hypertension, co-morbidity is substantial.5

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Ray A, et al.

Possible mediators linking hypertension and cancer

Nitric oxide (NO) has an important pathophysiological role
in both hypertension and cancer.6 NO, in several biological processes and diseases, enables or enhances angiogenesis. Angiogenic growth factors such as vascular endothelial growth
factor (VEGF) and fibroblast growth factor (FGF) induce NO
and require NO to elicit an effect.7 Further, NO modifies the
release of cytokines from macrophages. Moreover, there is
clear evidence of abnormalities in pulmonary NO levels of
patients with lung cancer and primary pulmonary hypertension.8 NO-generating enzyme, the endothelial nitric oxide synthase (eNOS), is expressed in vascular endothelium, airway
epithelium, and certain other cell types. The eNOS is an important component of vascular homeostasis and is activated
by bradykinin.9
The second mediator that may link hypertension and cancer is the renin-angiotensin system. Renin releases angiotensin
I from angiotensinogen which subsequently gets converted to
the biologically active angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II acts on both the peripheral blood vessels and the central nervous system to increase
blood pressure. In the central nervous system, rostral ventrolateral medulla has a large quantity of angiotensin-type 1 (AT1)
receptors and angiotensin II binds to these receptors to exert
its activity. Low-density lipoprotein cholesterol (LDL-C) has
been demonstrated to upregulate the AT1 receptor, leading to
increases in blood pressure.10 The role of the renin-angiotensin
system in tumor angiogenesis is little understood. Both angiotensin II and AT1 receptors have been shown to stimulate
angiogenesis.11,12 Angiotensin II induces VEGF, thereby playing
an important role in VEGF-mediated tumor development and
angiogenesis.11 Similarly, the AT1 receptor pathway supports
tumor-associated macrophage infiltration, which results in
enhanced tissue VEGF protein levels, angiogenesis and growth
of tumor cells.12
Epidemiological association between cancer and hypertension
Several studies have shown a relationship between hypertension and an increased cancer risk. High blood pressure is
associated with increased risk of lung cancer in male hypertensive smokers.13,14 However, the studies were unable to
qualify hypertension per se as an independent risk factor. An
increased risk of breast cancer has been seen in hypertensive
women and men.15-18 Also, the prevalence of dyslipidemia/
hypercholesterolemia was higher in breast cancer patients.17,18
Amongst gynecological cancers, patients with endometrial
cancer frequently have a history of hypertension.19,20 Similarly,
steroid hormone dependent tumors i.e., prostate cancer and
fast-growing benign hypertrophy of the prostate are associated with high systolic and diastolic blood pressures.21 Further, several studies have demonstrated that hypertension was
associated with renal and colorectal neoplasia.22-24 Moreover,
it has been observed that hypertension was associated with
an increased risk of mortality from cancer and the overall survival was decreased by hypertension.3,25 Whether the coexistence of cancer and hypertension is a mere association or bears
a real cause and effect relation, needs to be explored.

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Factors influencing angiogenesis in hypertension and cancer

Angiogenesis is a prominent feature of cancer and its abnormality appears to play an important role in hypertension.26
Different important pro-angiogenic factors have been shown
to be associated with hypertension. Compared with healthy
controls, patients with hypertension have elevated plasma levels of VEGF.27,28 Also, VEGF protein expression was much higher
in hypertensive than in normal rats.29 Similarly, many studies
have observed an increase in the plasma levels of basic
fibroblast growth factor (bFGF) and tumor necrosis factor-alpha (TNF) among hypertensive patients.30-32 Moreover, after
stimulation with angiotensin II, the secretion of interleukin-1
beta (IL-1 beta) by peripheral blood monocytes was shown to
be increased significantly in hypertensive patients than healthy
individuals.33 Several studies have demonstrated that the
plasma interleukin-6 (IL-6) concentration was positively associated with hypertension. 34-36 IL-6 is a multifunctional
cytokine produced by macrophages, T-cells, B-cells, endothelial cells and tumor cells. IL-6 is able to promote tumor growth
by upregulating antiapoptotic and angiogenic proteins in tumor
cells.37 On the other hand, hypertension activates endothelial
cells to increase the expression of IL-6, IL-8 and TNF and
induces neutrophil and monocyte adhesion and migration.38
Also, inflammatory markers of monocyte-endothelial cell interaction are elevated in hypertensives in comparison to
normotensives.39
Studies over the past 30 years have established that the
development of new capillaries from an existing vascular network (angiogenesis) is an essential component for the growth
of primary and metastatic solid tumors. Malignant tumors do
not grow beyond 2-3 cubic mm in size unless they stimulate the
formation of new blood vessels and thus provide a route for the
increased inflow of nutrients and oxygen, and outflow of waste
products. Tumor angiogenesis also provides an essential exit
route for metastasizing tumor cells from the tumor to the blood
stream. Angiogenesis is a complex, multistep process driven
by many local signals within the tumor.40 Both pro-angiogenic
and antiangiogenic factors secreted by the tumor, inflammatory and stromal cells play an important role in the regulation
of neovascularization (Table 1). Among the most important of
these is VEGF, a specific mitogen for endothelium, which increases vascular permeability and induces proteolytic enzymes
necessary for vascular remodeling.41 The low oxygen tension
(hypoxia) present in the tumors is known to upregulate the expression of VEGF by tumor cells. Human macrophages also respond to hypoxia by increasing their release of VEGF in vitro.
Moreover, macrophages are accumulated in higher numbers in
poorly vascularized than highly vascularized areas of tumors.42
Therefore, the microenvironmental hypoxia that arises as a consequence of the development of a solid tumor also acts to promote tumor growth. Apart from inducing the expression of key
factors of the angiogenic signaling cascades, hypoxia at the cellular level mediates the infiltration and accumulation of tumorassociated macrophages within avascular tumor regions. Complex interactions between tumor cell and macrophage hypoxiaregulated gene products and their associated pathways form
the basis for the promotion of tumorigenesis and malignant progression.43

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Hypertension and cancer

Table 1
Factors influencing angiogenesis
Pro-angiogenic factors

aFGF, adrenomedullin, angiogenin, angiopoietin 1,

angiopoietin 2, angiotensin II, bFGF, bradykinin, chymase,
COX-2, ENA-78, eotaxin, Eph/Ephrins, EGF, estrogen,
fractalkine, GCP-2, G-CSF, GM-CSF, GRO, GRO, HGF,
I-309, IGF-I, integrin3, integrin5, IL-4, IL-6, IL-8, IL13, leptin, MMP-1, MMP-2, MMP-9, midkine, MCP-1, NO, PAF,
PIGF, plasminogen activator, PBP-2, PD-ECGF, PDGF,
pleiotrophin, proliferin, PGE1, PGE2, SDF-1, thrombin, Tie-2,
TGF, tryptase, TNF, VEGF.

Factors having both pro- and

anti-angiogenic functions
GRO, IL-1, TGF-.

Antiangiogenic factors

6Ckine, angiostatin, BCA-1, chondromodulin 1,

endostatin, sFGF R, IFN, IFN, IFN, IP-10,
IL-10, IL-12, I-TAC, MIG, NO, PEDF, PAI-1, PAI2, PF-4, suramin, thrombospondin 1,
thrombospondin 2, TIMP-1, TIMP-2, TIMP-3,
TIMP-4, troponin-I, vasculostatin, vasostatin,
VEGI.

Macrophages are supposed to play a key role in tumor angiogenesis. By release of VEGF, bFGF, transforming growth factor-alpha (TGF-alpha), IL-1, IL-6, IL-8 and TNF, activated
macrophages have the capability to influence each phase of
the angiogenic process, such as alterations of the local extracellular matrix and stimulation of vascular endothelial
cells.40,44,45 The tumor-infiltrating macrophage density correlates significantly and positively with intratumor microvessel
counts and negatively with patients survival.46 Quantification
of microvessel density in the tumor specimen correlates with
either metastasis or recurrence in many malignancies such as
breast and lung cancer.47 Several studies have shown that the
number of infiltrating macrophages were significantly associated with VEGF expression.41,48 On the other hand, VEGF has
also been found to stimulate migration in macrophages. Thus,
VEGF expression may be an important factor in the recruitment of tumor-associated macrophages.49 Further, some recent studies showed an association between the mutation of
p53 protein and VEGF expression.50,51 It appears that VEGF is
a major regulator of angiogenesis and vasculogenesis.
Antiangiogenic drugs
Angiogenesis begins with local degradation of the basement membrane-surrounding stroma by the endothelial cells
in the direction of the angiogenic stimulus (Figure 1). It has
already been mentioned that endothelial invasion is regulated
by different autocrine and paracrine factors. Malignant invasion and physiological invasion share some common gene products and signaling cascades. Understanding the difference in
gene expression in the development of the pro-angiogenic and
invasive phenotype is an important step towards therapeutic
targeting. Nevertheless, certain chemotherapeutic agents have
potent antiangiogenic properties, which may be a part of their
antitumor activity. Among taxanes, paclitaxel (taxol) and
docetaxel (taxotere) have antiangiogenic activity.52 However,
docetaxel appears to be more potent at inhibiting angiogenesis. 53 Similarly, anticancer drugs such as vinblastine 54
temozolomide55 and doxorubicin56 are capable of inhibiting
angiogenesis. On the other hand, antiangiogenic therapy using angiogenesis inhibitors is a relatively new and promising
area of cancer treatment that specifically inhibits new blood
vessel formation within the tumor. Physiologically, angiogenesis occurs during embryogenesis, wound healing and repro-

Figure 1: Process of angiogenesis

ductive functions in adults. The architecture of tumor vessels

is fundamentally different from that found in healthy tissues.
Tumor vessels are usually irregular, heterogeneous, leaky, and
poorly associated with stromal cells.57 Endothelial cells in
tumor vessels are also disorganized and express imbalanced
surface molecules. In animal tumor models, several angiogenesis inhibitors seem to inhibit specifically tumor angiogenesis without having obvious effects on the normal vasculature.58 More than 60 angiogenesis inhibitors are being evaluated for their anticancer effects in patients.57
Several classes of angiogenesis inhibitors that target different steps involved in angiogenesis include59: (1) Drugs inIndian J Pharmacol

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Ray A, et al.

hibiting matrix breakdown, the matrix metalloproteinase inhibitors, such as matrimastat, prinomastat and neovastat. (2)
Drugs that block endothelial cell signaling via VEGF and its
receptor like antiVEGF antibodies. (3) Drugs that are similar
to endogenous inhibitors of angiogenesis including endostatin,
angiostatin, interferons and IL-12. (4) Thalidomide and its
analogs have been shown to inhibit growth factor-induced
neovessel formation. Moreover, (5) drugs such as celecoxib,
rofecoxib, squalamine, fumagillin analog, and those targeting
the integrins are also being evaluated as angiogenesis inhibitors.
Non-steroidal antiinflammatory drugs (NSAIDs), particularly selective cyclooxygenase-2 (COX-2) inhibitors such as
celecoxib or rofecoxib have been shown to inhibit angiogenesis.60,61 COX-2 catalyzes the synthesis of prostaglandins from
arachidonic acid and there is evidence that it may promote
tumor angiogenesis.60 COX-2 is upregulated in cancer cells,
adjacent stromal cells and angiogenic endothelial cells during
tumor progression.62 There is enough preclinical evidence that
strongly supports the potential role of COX-2 inhibitors for the
prevention and treatment of cancer.60 On the other hand,
neovastat is another promising antiangiogenic drug purified
from shark cartilage.63 The drug is effective after oral administration and induces endothelial cell apoptosis, inhibits matrix metalloproteinase activities and VEGF-mediated signaling
pathways.64 Recently, it has been observed that a number of
thalidomide analogs act as antimalignant drugs due to their Tcell co-stimulatory, antiangiogenic and antiinflammatory effects. These thalidomide analogs are known as
immunomodulatory drugs and include revimid and actimid.
Further, the other class of analogs termed as selective cytokine
inhibitory drugs (SelCIDs) are phosphodiesterase 4 inhibitors.
They do not stimulate T-cells. These analogs have been evaluated for their ability to inhibit tumor angiogenesis, vascularity
and growth.65,66
Antihypertensive agents and angiogenesis
Interestingly, bradykinin facilitates growth in many cancers by increasing tissue permeability and stimulating angiogenesis. Certain peptide and non-peptide bradykinin antagonists show potential anticancer properties by inhibiting angiogenesis (VEGF-mediated) and membrane metalloproteinase
activity (MMP-2 and 9).67 It is well known that bradykinin is an
important component of physiological blood pressure lowering system. Several antihypertensive drugs have effects on
the process of angiogenesis. 68 In general, drugs such as
atenolol, diltiazem and enalapril do not affect in vitro angiogenesis in humans within therapeutic ranges.69 On the other
hand, drugs like mibefradil70 (calcium channel blocker) and
terazosin71 (1-blocker) show direct antiangiogenic activity.
Similarly, angiotensin-converting enzyme (ACE) inhibitors such
as captopril and perindopril have been shown to inhibit angiogenesis.72,73 Perindopril, which was shown to be a potent inhibitor of the growth of hepatocellular carcinoma and angiogenesis, also suppresses VEGF at clinically relevant doses.73
On the contrary, it has been observed that the very low dose
combination of perindopril and indapamide (a non-thiazide
sulfonamide diuretic) induces neovascularization.74 Similarly,
ACE inhibitor quinaprilat, an active metabolite of quinapril,
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promotes angiogenesis.75 Moreover, studies have recorded that

angiogenesis was induced by administration of the 1-blocker
prazosin76 and calcium channel blocker amlodipine.77 An increased concentration of VEGF was found in relation to the
duration of prazosin treatment.76
Angiotensin II and neovascularization
The formation of new blood vessels is a necessary physiological process in embryonic development and in repair
mechanisms such as wound healing, tissue repair following
ischemia and cyclical changes in the endometrium during the
menstrual cycle.78 On the other hand, lack of blood vessel
growth leads to many pathological conditions such as bowel
atresia, unilateral facial atrophy, peptic ulcers, ischemic heart
disease and peripheral vascular disease.78,79 Cardiovascular
researchers have been exploring the feasibility of enhancing
angiogenesis and thereby collateral vessel formation in patients with chronic ischemia of the myocardium or lower limb,
by increasing the local concentrations of angiogenic growth
factors either by giving recombinant protein or by gene transfer, or by administering endothelial progenitor cells that synthesize a cocktail of growth factors for angiogenesis.80
By a complex mechanism, the renin-angiotensin system is
involved in preserving the blood supply to organs in order to
maintain normal cellular functions.81 Experimental evidence
also indicates that angiotensin II tends to restore blood flow
to the ischemic tissues and plays an important role in angiogenesis and thereby in maintaining tissue perfusion during
sustained ischemia.81,82 Angiotensin II, the main effector peptide of the renin-angiotensin system, is implicated in the development of hypertension and exerts its actions through AT1
and AT2 receptors.83 Several investigators have demonstrated
the positive role of angiotensin II and AT1 receptors in tumor
angiogenesis,11,12,81 and the antiangiogenic effects of ACE inhibitors and AT1 receptor antagonists.68,72,73 On the other hand,
some of the ACE inhibitors reportedly promote angiogenesis75
by slowing down bradykinin degradation and an obscure differential effect on the expression of AT receptors.81,84 Interestingly, many researchers have suggested that hypertension
might influence cancer through vasoactive chemicals like angiotensin II.85,86 Moreover, inhibition of tumor growth and angiogenesis by ACE inhibitors87,88 indicates the role of angiotensin
II as an angiogenesis promoting factor and its probable influence in the pathological process of cancer. Impaired angiogenesis may be due to some inherent problem of endothelial
cells (signaling defect), which leads to defective response to a
high level of pro-angiogenic factors in hypertension7,78,89,90 and
probably, high levels of these factors promote cancers as discussed earlier. In spite of a considerable number of studies
over the past several years, the association between hypertension and the risk of cancer remains obscure.3,85,86,91 Similarly, several aspects of the relationship between hypertension and angiogenesis are controversial.27,78
Antihypertensive drugs and cancer
Interestingly, antihypertensive treatment may promote
cancer through unknown mechanisms.92 Analysis of various
epidemiological, cohort and randomized studies of antihypertensive drugs shows that long-term use of some antihyper-

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Hypertension and cancer

tensive drugs while preventing cardiovascular complications

has been associated with increased risk of cancer. The most
convincing evidence exists for the association between the use
of diuretics and renal cancer.93 A recent study has shown that
the use of immediate-release calcium channel blockers, thiazide diuretics, and potassium-sparing diuretics were associated with increased risk of breast carcinoma.94 Reserpine has
been implicated in the development of breast cancer.92,93 Another study has documented higher mortality from lymphatic
and hematopoietic cancers in drug-treated hypertensive
women as compared to normal women, and higher mortality
from cancers of the uterus, cervix and ovary in those who
were on antihypertensive treatment.95 Furthermore, several
calcium channel blockers have been shown to block apoptosis
in animal and in vitro studies.96 On the basis of these observations, it has been hypothesized that calcium antagonists may
function as cancer promoters and that they might cause cancer in humans. However, conflicting reports on the use of calcium channel blockers and the occurrence of cancer have been
observed.92,96-98 Similar conflicting results were observed in
case of atenolol and ACE inhibitors with reference to the risk
of cancer.99,100 Overall, the findings of different studies on the
association between antihypertensive medications and the
development of cancer are contradictory.

References

Conclusions

12.

A substantial number of cancer patients have cardiovascular co-morbidity, particularly hypertension. These two distinct diseases, i.e., cancer and hypertension, can share some
common pathophysiological mediators, and through these,
hypertension might influence the promotion of tumorigenesis
and malignant progression. Several studies documented an
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observation is somewhat clearer in the case of lung cancer,
which is the most common cancer in the world including
America and Europe. An increased risk of lung cancer has been
noticed among hypertensive smokers. However, the process
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plays a significant role in both hypertension and cancer. Different important pro-angiogenic factors such as VEGF, bFGF,
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tumor, inflammatory and stromal cells. The level of angiogenic
factors is high in hypertension. Among inflammatory cells,
monocytes/macrophages demonstrate wide heterogeneity in
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Macrophages are terminally differentiated cells that produce
a number of potent angiogenic cytokines and growth factors,
and influence various stages of angiogenesis. Recently, some
studies have demonstrated that the renin-angiotensin system
plays an important role in VEGF-mediated angiogenesis. In
experimental cancer therapy, inhibition of angiogenesis has
become a major goal to block the tumor growth. This therapeutic approach requires a precise knowledge of angiogenesis. In this context, more studies at the basic biological level
may improve our understanding about the relationship between
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Indian J Pharmacol

| October 2004 | Vol 36 | Issue 5 | 341-347

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