Tumor‐infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer

Abstract

Inflammatory breast cancer (IBC) isInflammatory breast cancer (IBC) is clinically characterized by rapid tumor enlargement with skin erythema. The disease tends to invade locally and metastasize systemically and the histopathologic features are consistent with an extremely aggressive phenotype. 1 Despite recent advances in strategies for multimodal treatment of patients with IBC, this disease is still considered incurable and there is a great need for further improvement of treatment strategies to combat this breast cancer variant. 2 With most solid tumors, growth, proliferation and metastasis are thought to be dependent on angiogenesis, a process in which vessels grow, in part, by incorporating circulating endothelial cells (ECs) and endothelial precursor cells (EPCs). [3][4][5][6][7][8][9][10] Studies have shown that soluble Flt-1 (sFlt-1) can inhibit vascular endothelial growth factor (VEGF) activity not only by sequestering VEGF but also apparently via a dominant negative mechanism in which it forms heterodimers with the full-length membrane-spanning receptors Flt-1 and KDR and thereby prevents VEGF-dependent transphosphorylation and activation of these receptors. 11-15 Soluble Tie2 (sTie2), an artificial form of Tie2 (a full-length membrane-spanning receptor), is a heparin-binding protein that complexes with angiopoietin (Ang) with the same affinity and specificity as Tie2. 16 -18 In the present study, we transfected tumor cells with genes for sFlt-1 and sTie2, assessed the effects of these genes in association with tumor-infiltrating (TI) ECs/EPCs in IBC xenografts and found that VEGF and Ang pathways are crucial in IBC angiogenesis and metastasis. The present results help to clarify the mechanism of induced migration of ECs/EPCs into IBC nests and the effects on IBC of blocking VEGF and Ang pathways.

Pericytes and Endothelial Precursor Cells: Cellular Interactions and Contributions to Malignancy

“…Vascular endothelial growth factor (VEGF)-mobilized stem cells restored tumor angiogenesis and growth in Id-mutant mice (11). Clinically, a higher population of EPC is associated with inflammatory breast tumors versus a noninflammatory phenotype (12). Additionally, EPC have been detected in the circulation and malignant tissues of patients with multiple myeloma (13).…”

Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression

“…Recently, using a semiquantitative reverse transcriptase polymerase chain reaction, Shirakawa et al (2002b) showed that angiogenic, but not lymphangiogenic factors are overexpressed in resected specimens of 19 IBC patients when compared with 23 non-IBC tumours. In the same study, a significantly higher population of tumour-infiltrating endothelial cells or endothelial precursor cells was immunohistochemically found in the tumourassociated stroma of IBC specimens than in non-IBC specimens.…”

Angiopoietin-2 decreases vascular endothelial growth factor expression by modulating HIF-1α levels in gliomas

“…The expression of Tie2 was believed to be confined to vascular structures (Yancopoulos et al, 2000). However, recent studies have identified Tie2 expression in nonvascular tissues, as in the hematopoietic system and in the nonvascular compartment of several types of cancer (Kukk et al, 1997;Shirakawa et al, 2002;Wang et al, 2005). Recently, our group reported Tie2 expression in neoplastic astrocytic cells in malignant human gliomas (Lee et al, 2006b).…”