Angiogenesis is the growth of new blood vessels and is a key process which occurs during both physiological and pathological disease processes. Knowledge of the mechanisms through which this process is initiated and maintained will have a significant impact on the many of the solid tumors in field of medical oncology . Pathological angiogenesis occurs in major diseases such as cancer, diabetic retinopathies, age-related macular degeneration and atherosclerosis.
Keywords: Angiogenesis; Medical oncology; Solid tumors
Approval of several antiangiogenesis drugs for systemic therapy for several malignances have been developed, like bevacizumab a humanized monoclonal antibody to vascular endothelial growth factor VEGF, however the success of bevacizumab in combination with chemotherapy in metastatic breast cancer and metastatic colorectal cancer is well established and as monotherapy of bevacizumab in case of metastatic renal cancer approved till date. Era of antiangiogenic drugs began with the landmark article published in 1971 in NEW ENGLAND JOURNAL OF MEDICINE by Folkman , the content of above publication was given below,
i. Solid tumors will not grow beyond 2mm in size unless they induce and sustain new blood supply to provide oxygen and nutrients for their growth of tumor mass.
ii. Up to 2mm size tumor may derive its oxygen and nutrients by passive diffusion.
iii. When tumor cell population begins to produce TAF tumor angiogenic factors which creates revascularizations by endothelial cells these endothelial cells of nearby preexisting blood vessels began to migrate, divide and formed tubular structures to form new blood vessels these blood vessels infiltrate in tumor mass to established new blood supply for the progress of tumor growth.
iv. Administration of antiangiogenesis agents for example Anti TAF tumor angiogenesis factor specific neutralizing antibodies will block tumor angiogenesis process , but such tumor shrinkage would never be completely because microscopic tumor which size 2mm or less can survive without new vessels so this type of therapy never be called curative Dr Folkman further described in his reports following- He described nature of angiogenic switch present in tumors ,first stimulator of angiogenesis, are Basis fibroblast growth factor and discovery of several endogenous antiangiogenesis inhibitors, after so many twist and turns ,the concepts of therapeutic role of angiogenesis has been finally formulated,
a. Certain angiogenic drugs seems to have no clinical benefits when used as
b. monotherapy but does have good role when it is combined with chemotherapy drugs.
c. In addition to stimulators of angiogenisis process there are number of endogenous antiangiognisis factors down regulatory effect on them can lead to progress of tumors.
d. Angiogenesis can also contribute to growth of liquid tumors like hematological malignancies not just for only solid tumors due to expression of number of growth factors like cytokines, cytokinines by activated endothelial cells at newly formed blood vessels sites, as well as bone marrow which promote survival and growth of tumor cell populations .
e. There are no single TAF, rather large numbers of
molecules involved in angiogenesis process (Figure 1).
There are number of sequential events involved in the
development of new capillary blood vessels in ongoing tumor mass.
The first step in the formation of new blood vessels is breaking of
basement membrane of parental venule (pre-existing small blood
vessels) that create moment of endothelial cells towards adjacent
tumor cells this process stimulated by proangiogenic factors
secreted by tumor cell mass, these proangiogenic factors Known
as Matrix metalloproteinase and urokinase plasminogen activator.
(They are basically proteolysis enzymes) This philosophy of above
two enzymes (proangiogenic factors) leads to research to form
drugs which inhibit such enzyme. Second step in formation of new
blood vessels is migration of endothelial cells as well as division of
these mature endothelial cells adjacent to tumor moss and finally
formation of new basement membrane of juvenile blood vessels
these new angiogenic blood vessels of tumor cells established the
further growth of tumor cells populations , apart from this some
endothelial proginator cells formed in bone marrow from here
these goes to main blood vessels supply via this these proginators
reaches to tumor cell mass to stimulate division of mature
endothelial cells in order to form new blood vessels.
Pericytes is a single layer of periendothlial smooth muscle
cells which modulate endothelial cell functions and critical for the
development of mature vascular network since role of pericytes in
helping survival of endothelial cells thus pericytes emerged as an
important therapeutic target for antiangiogenic therapy .
Several angiogenic growth factors found which modulates
tumor angiogenesis some working directly some working
indirectly thus divided as,
i. Directly acting factors
ii. Indirectly acting growth factors.
Directly acting growth factors include VEGF family include
Tyrosin kinase, angiopoetine, notch singling receptor specially
notch 4, NOTCH 4? is a member of notch family is basically a
TRANS MEMBRANE RECEPTOR express primarily on endothelial
cells of blood vessels .All factors have high degree of specificity
for endothelial cells associated neovascularization. VEGF another
name is VPF vascular Permeability factor, VEGF produced by
primary tumor cells, macrophages , platelets cells , VEGF also
plays role in normal physiological functions such as bone marrow
formation, Haemopoiesis, wound healing not only limited to
solid tumors but also hematological malignancies leukemia’s and
lymphomas . Types OF VEGF -VEGF 1,VEGF 2 ,VEGF3 OUT OF
THAT VEGF 1 AND 2 regulate angiogenesis and VEGF regulate
lymph angiogenesis, . VEGF is protein with vascular permeability
that is secreted by tumor cells. Indirectly acting angiogenic factors
those who amplify angiogenic process are TNF a and TNF b,
Transforming growth factors, Inflammatory cytokinines such as
IL6 and IL8, Granulocyte stimulating factor, PDGF platelet derived
growth factor, estrogen and androgen hormone as well. VGEF was
discovered in 1989 and replaced to be highly specific and potent
mitogen for vascular endothelial cells (Figure 2).
There are four roles of VEGF by which it promotes tumor
angiogenesis it can stimulate endothelial cells division and
induce endothelial cells migrations also enhanced endothelial
cells survival and mobilizes endothelial progenitors cells from
bone marrow to the site of tumorogenesis, elevated expression
of VGEF commonly associated with tumor hypoxia so hypoxia
in tumor cells leads to over expression of VGEF thus leads to
neovascularization of tumor cell mass  (Figure 3).
In addition to multiple factors stimulating the angiogenesis
there are inhibits molecules of angiogenesis process as well that
inhibitor is a large glycoprotein molecule present in Extracellular
matrix named Trombospondin-1 (TSP-1) P53 gene was found
to regulate TPS-1 level, loss of P53 gene associated with down
regulation of TSP-1 expression. Second inhibitor is VASOINHIBIN
a protein which is secreted by Endothelial cells and stimulation of
angiogenic factors VEGF, the Biology of Endogenous angiogenesis
inhibitors is that they maybe induce by other cancer therapy to
have added effect for example some antiangiogenic treatment
strategy such as low dose metronomic chemotheraphy or
doxycycline are known to induce elevated levels of TSP-1 .
Most obvious strategy would be development of drugs
that neutralize proangiogenic growth factors such as VEGF.
All approved antiangiogenic drugs either block VEGF or VEGF
tyrosin kinase receptor example Bevacizumab drug developed to
neutralize VEGF in addition to antibody/protein therapy a large
number of small molecule and receptor tyrosin kinase inhibitors
have been developed to block VEGF receptor phosphorylation
such drugs are SUNITINIB and SORAFENIB these drugs action
is not only inhibition of angiogenesis but also, they directly act
by inhibition of tumor cell. Bevacizumab when bevacizumab
treatment would be more helpful, use alone not effective but
when use along chemotherapy drugs they prove to have good
results, other mode of treatment and drugs those having
antiangiogenic effect or example radiation treatment, Cetuximab
or Transtuzumab (targeting Her-2 antibody) do have down
regulatory effect on VEGF and up regulatory effect on TSP-1.
How antioangiogenic drugs enhanced the effects of radiation and
chemotherapy? Antioangiogenic drugs actually increase tumor
oxygenation and blood supply thus increase intratumor level of
chemotherapy as well as increase oxygen level also increases the
effects of radiotherapy .
Possible markers of tumor angiogenesis are circulatory
blood proteins VEGF, Proangiogenic growth factors, circulatory
endothelial progenitors cells . Biomarkers are elevated levels
of VEGF are associated with poor prognosis, thus if high levels
of VEGF, bevacizumab treatment would be more helpful ,
VEGF receptors diagnosis and test require tissue specimen for
immunohistochemistry study, but the tissue specimen must be
B- Blockade OF development of endothelial progenitor cells
C- Normalization of vasculature thus decrease permeability of
and increase chemotherapy drug delivery to tumor tissue.
D- Direct effect on tumor as antitumor effect.
E- E-Inhibition of damage of endothelial cells by chemotherapy
F- F-Immunomodulatory effect. For the tumors other than
renal cell carcinoma anti VEGF therapy only provide benefits
when it given in combination with chemotherapy drugs ,Tyrosin
kinase inhibitors in metastatic colorectal cancer enhanced its
effect when given with chemotherapy drugs like metastatic breast
cancer bevacizumab augments the effects of paclitaxil based
iv. 4- Anti thrombotic events Hypertensions do occur due
to anti VEGF causes inhibition of endothelial cells derived nitric
oxide which is known vasodilator. Why cause protein urea because
it causes damage to vascular endothelial cells of glomeruli which
leads to protein urea Gastro intestinal perforation do occur in
1.5 to 5.5 % patients receiving bevasuzimab , because it causes
GI ulceration which further leads to gastrointestinal perforations
Bevasuzimab induces VEGF inhibition which results in cholesterol
emboli syndrome CES (HTN, GI PERFORATION, ESIONOPHELIA)
which leads to mesenteric vessels ischemia which further leads
Basis of angiogenesis within the tumor ecosystem cellular
and molecular components is provided. Clinical evidence has
demonstrated the effectiveness of traditional vessel-directed
antiangiogenics, stressing on the important role of angiogenesis
in tumor establishment, dissemination, and growth. Particular
focus is placed on the interaction between tumor cells and their
surrounding ecosystem, which is now regarded as a promising
target for the development of new antiangiogenics drugs which
having proving benefits in colorectal cancer , breast cancer as well
as in lung cancer (NSCLC) Non-small cell lung carcinomas.