Angiopoietins and Their Role in Colon Cancer Angiogenesis

Angiopoietins and Their Role in Colon Cancer Angiogenesis

ABSTRACT: Tumor angiogenesis is a complicated process that is regulated by numerous factors simultaneously and in a coordinated fashion. Angiogenic factors drive the process of neovascularization, but the initiation of angiogenesis involves priming of endothelial cells so that they will respond to mitogenic stimuli. The angiopoietins (Ang) -1 and -2 mediate endothelial cell stability through binding to their endothelial cell-specific receptor, Tie-2. Ang-1 leads to endothelial cell stability, and, in vivo, to an actual decrease in angiogenesis. This is likely due to its ability to enhance adhesion to the perivascular tissues. In contrast, Ang-2 leads to endothelial cell instability and may be an initiating factor in angiogenesis, priming endothelial cells for mitogenic signals. Thus, a novel antiangiogenic strategy may be one that leads to enhanced endothelial cell stability, thereby protecting endothelial cells from standard angiogenic stimuli. This may ultimately lead to tumor dormancy by transforming a rapidly growing tumor into an indolent tumor. [ONCOLOGY 16(Suppl 3):31-35, 2002]

Angiogenesis, a process of blood vessel formation
whereby new vessels sprout and mature from the preexisting vasculature,[1] is
required for a variety of physiologic processes, including pregnancy, wound
healing, tissue repair, and organ regeneration. Angiogenesis also contributes to
the development of pathologic conditions such as cancer progression and
metastasis, diabetic retinopathy, psoriasis, atherosclerosis, and rheumatoid
arthritis. [2,3]

Angiogenesis is a complicated process that is regulated by numerous factors
that occur simultaneously and in a coordinated fashion. The process of
angiogenesis requires that endothelial cells (ECs) detach from pericytes and the
extracellular matrix (ECM), proliferate, migrate, and form capillary tubes that
connect to other newly developed vascular tubes.[4] The result is a primitive
yet functional vascular network. Recent evidence indicates that the presence of
specific cytokines mediates EC "stability/instability." [5] These
factors either protect EC from undergoing apoptosis or facilitate EC
"instability" that allows the response to mitogenic factors. The
angiopoietins are a family of proteins that mediate EC stability and survival. A
better understanding of the biologic effects of angiopoietins in the angiogenic
process may contribute to the development of novel therapeutic strategies.

Angiopoietins and Their Tyrosine Kinase Receptor, Tie-2

The angiopoietins are a family of growth factors identified as being specific
for the vascular endothelium. The specificity of the angiopoietins for the
vascular endothelium results from the restricted distribution of the
angiopoietin tyrosine kinase receptor Tie-2 (also known as TEK [6]) to
endothelial cells. Four different angiopoietins—Ang-1 through Ang-4—have
been described.[7-9] The best characterized of these are Ang-1 and Ang-2. Ang-1
exerts its biologic effect by binding to Tie-2, inducing phosphorylation of
Tie-2.[10,11] Ang-1 also may control the ability of ECs to stabilize the
structure and modulate the function of blood vessels. In vivo analysis by
targeted gene inactivation revealed that Ang-1 recruits and sustains
periendothelial support cells.[12] Ang-2 is antagonistic to Ang-1 and also binds
to Tie-2, but it does not typically induce phosphorylation. However, at
supraphysiologic doses, Ang-2 also may initiate EC signaling and survival.[13]
Tie-1 is an orphan receptor, but its ligand has not been identified.

Several investigators have demonstrated in vitro that Ang-1 serves as a
survival factor for ECs. Kwak and associates [14] examined the effect of Ang-1
on apoptosis in human umbilical vein ECs (HUVECs). Ang-1 dose-dependently inhibited apoptosis under serum-deprived conditions, with
significant inhibition occurring with Ang-1 doses as low as 50 ng/mL.
Furthermore, the addition of 20 ng/mL VEGF (a potent angiogenic factor known
also to be an EC survival factor) to 200 ng/mL Ang-1 augmented the antiapoptotic
effects of Ang-1, suggesting that Ang-1 acted in conjunction with VEGF.

Similar results were obtained by Papapetropoulos et al,[15] who also
demonstrated dose-dependent stabilization of HUVEC network organization by
Ang-1. In addition, these authors demonstrated that this response was indeed
dependent on Tie-2 activation, as addition of a soluble form of Tie-2, but not
Tie-1, completely blocked the effects of Ang-1. It was also demonstrated that
the signaling pathway by which Ang-1 protects ECs from apoptosis is likely
through phosphorylation of the survival serine-threonine kinase, Akt. [16,17]
This finding occurred in association with the up-regulation of the apoptosis
inhibitor, survivin, in ECs and protection of endothelium from apoptosis.[16] In
addition, transfection of a dominant-negative survivin construct abrogated the
ability of Ang-1 to protect cells from undergoing apoptosis. These data suggest
that the activation of antiapoptotic pathways mediated by Akt and survivin in
ECs may contribute to Ang-1 stabilization of vascular structures during

It is likely that Ang-1 works in conjunction with VEGF to help stabilize
vascular networks. Ang-1 appears to recruit periendothelial support cells, [12]
and this interaction may be required for EC survival. This is supported by
evidence showing that Ang-1 knockout embryos are able to undergo VEGF-dependent
angiogenesis, but ECs are unable subsequently to interact with periendothelial
support cells.[12] This deficit leads to vascular regression. Ang-2 is
antagonistic to Ang-1 and thus leads to EC destabilization. In the presence of
VEGF, this destabilization leads to robust angiogenesis.[18]

Inhibition of the activity of the Angs by soluble Tie-2 has been investigated
as a method of inhibiting angiogenesis. Lin and colleagues[19,20] constructed an
adenoviral vector containing the mouse extracellular domain coding region of
Tie-2, which can systemically deliver recombinant soluble Tie-2 (AdExTek)
capable of blocking Tie-2 activation. Administration of soluble Tie-2 (AdExTek)
inhibited the growth in both primary and metastatic tumors in mice. However, it
is unclear whether the observed effects are due to sequestration of Ang-1 or


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