Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis

Abstract

Summary Endothelial receptor tyrosine kinases may play important roles in pathological vascular growth, particularly in tumours. In this study, immunohistochemistry was used to evaluate the expression of a novel endothelial receptor tyrosine kinase, Tie2/Tek, in the endothelium of vascular 'hotspots' in normal breast tissue (n = 10), benign breast lesions (n = 10) and in breast tumours (n = 123). Tie2 expression was detected in the endothelium of all breast tissues examined. However, the strongest expression of Tie-2 was seen in vascular 'hot spots' within the inflammatory infiltrate at the periphery of invasive tumours. Moreover, the proportion of Tie2-positive vessels (Tie2 counts/CD31 counts) was significantly higher in breast tumours than the proportion of Tie2-positive vessels in either normal breast tissue or benign breast lesions (P = 0.004 and 0.0001 respectively). These data are consistent with a role for Tie2 in tumour angiogenesis and demonstrate the potential use of Tie2 expression as a novel marker of the tumour vasculature.

Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells

“…Other differences involve expression of the receptors tissue factor, a V b 3 and Tie-2 on the vascular endothelial cells of solid tumors but not of normal tissues. [9][10][11][12][13][14][15][16] The kinetics of solid tumor growth has three phases: an initial phase of slow growth, a second phase of more rapid growth and a third phase of slow growth. 7 This growth pattern was shown to fit a mathematical function 7 that was interpreted in terms of variable rates of 'birth' and 'death' of tumor cells between the interior and periphery of the tumor as growth progresses.…”

Angiopoietin-2 Is Implicated in the Regulation of Tumor Angiogenesis

“…4 -6 Key endothelial cell-specific growth factor receptors include the vascular endothelial growth factor (VEGF) receptors 1 (Flt1) 7,8 and 2 (Flk1) 9 and the Tie receptor tyrosine kinases (RTK), Tie-1 and Tie-2. 10 -15 Tie-2, which is expressed in the normal vasculature 16 and is up-regulated in tumor angiogenic vessels, 17,18 has at least two known ligands, angiopoietin (Ang)-1 and -2. 15,19,20 Stimulation of Flk1 and Flt1 by VEGF, respectively, promotes endothelial cell migration/ proliferation and tube formation.…”

Molecular Mechanisms of Tumor Angiogenesis

“…There is a decrease in sprouting and remodeling of the primitive vascular network, leading to restricted growth of the head and heart, together with a loss of heart trabeculation [58][59][60] . During normal physiological processes such as wound healing and pathological angiogenic states such as tumor vascularization, Tie2/TEK expression and activation are increased 56,57,61,62 , indicating a requisite role for this pathway in neo-angiogenesis. A paradigm incorporating interactions of VEGF and Ang1/2 in the development of normal embryonal and adult vasculature has been proposed 63 .…”

“…Vasculogenesis has long been thought of as a pre-natal stage vessel formation occurring exclusively in the developing embryo. H o w e v e r , r e c e n t d a t a h a s s p e c u l a t e d t h a t neovascularization in adult life, both in pathological and physiological conditions, can also occur by vasculogenesis [58][59][60][61] , and is particularly prevalent in large-solid cancers 62 .…”

“…Several studies have shown tumor-associated macrophages (TAM) to promote tumor angiogenesis and metastases 90 and extent of TAM correlates with increased tumor angiogenesis. These TAMs can in turn promote neovascularization 61 . To date only a few studies have focused on this area in solid tumors, and it has been suggested that a small subpopulation of monocytes expressing an angiogenic specific receptor tyrosine kinase, TIE2 expressing Monocyte (TEM), also play a very specific role in neo-vascularization of tumors 91 .…”