2002: Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft.
Cancer Res 2002 Jan 15;62(2):560-6, Shirakawa K, et al.
“In the present study, we examined hemodynamics in vasculogenic mimicry (VM) and angiogenesis of inflammatory breast cancer (IBC) xenografts (WIBC-9), having previously reported on the unique histological features and molecular basis of these processes (K. Shirakawa et al., Cancer Res., 61: 445-451, 2001). Histologically, the WIBC-9 xenografts exhibited invasive ductal carcinoma with a hypervascular structure (angiogenesis) in the tumor margin and VM without endothelial cells, central necrosis, or fibrosis in the tumor center. Results of molecular analysis indicated that WIBC-9 had a vasculogenic phenotype, including expression of Flt-1 and Tie-2. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-coursed dynamic micromagnetic resonance angiography analysis (with our newly developed intravascular macromolecular magnetic resonance imaging contrast agent), electromicroscopy, and immunohistochemistry, demonstrated blood flow and a VM-angiogenesis junction in the central area of the WIBC-9 tumor. It has previously been considered impossible to prove a connection between VM and angiogenesis using angiography, because there are no intravascular macromolecular magnetic resonance imaging contrast agents that do not exhibit significant leakage through the vascular wall. In the present study, laser-captured microdissection was performed in regions of WIBC-9 tumors that exhibited VM without endothelial cells, central necrosis, or fibrosis, revealing expression of human-Flt-1 and human-Tie2 and the absence of human-CD31, human-endothelin B receptor, and human-thrombin receptor. These facts led us to hypothesize that the VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between VM and angiogenesis.”
2002: Rapid Accumulation and Internalization of Radiolabeled Herceptin in an Inflammatory Breast Cancer Xenograft with Vasculogenic Mimicry Predicted by the Contrast-enhanced Dynamic MRI with the Macromolecular Contrast Agent G6-(1B4M-Gd)(256).
Cancer Res 2002 Feb 1;62(3):860-6, Kobayashi H, et al.
“The rapid blood flow and perfusion of macromolecules in the inflammatory breast cancer xenograft (WIBC-9), which exhibits a “vasculogenic mimicry” type of angiogenesis without the participation of endothelial cells and expresses high levels of the HER-2/neu antigen, was evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)]. Herceptin, which recognizes the HER-2/neu antigen and has similar size (10 nm) to G6-(1B4M-Gd)(256), accumulated and internalized in the WIBC-9 tumors more quickly than in the control MC-5 tumors that progress with normal angiogenesis. Three dimensional micro-MRI with the G6-(1B4M-Gd)(256) macromolecular MRI contrast agent distinguishes between the different types of angiogenesis and is predictive of the rapid accumulation and internalization of Herceptin in the WIBC-9 inflammatory breast cancer xenograft.”
2002: The Molecular Basis of Inflammatory Breast Cancer.
California Breast Cancer Research Program Symposium, Barsky SH, et al.
“Introduction: Inflammatory breast cancer (IBC) is a poorly understood, little studied form of breast cancer which is very aggressive and particularly devastating in disadvantaged minority women. IBC is characterized by florid tumor emboli within lymphovascular spaces, a phenotype which distinguishes it from other forms of breast cancer. The molecular basis of this phenotype is the focus of this research.
“Methods: Using a novel human-scid model of IBC, we have conceptually analyzed this phenotype in three parts.
“Results:
- The tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin / alpha-, beta-catenin axis which mediates tumor cell-tumor cell adhesion analogous to the embryonic blastocyst and accounts for both the compactness of the embolus and its complete dissolution with anti-E-cadherin antibodies, absent calcium, or E-cadherin dominant-negative mutant approaches. Dissolution of the tumor cell embolus by any of these approaches induces apoptosis via an anoikis pathway. The compactness of the embolus results in its resistance to chemotherapy / radiation therapy and its efficiency at metastasis formation and therefore therapeutic strategies which disadhere it are highly desirable.
- The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells because of complete absence of sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This natural tumor cell-endothelial cell aversion of the tumor cell embolus (IBC spheroid) further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. Experiments with purified glycosyltransferases which add sialyl-Lewis X/A to MUC1 on the IBC spheroids produce strong electrostatic repulsions which disrupt the E-cadherin homodimers and cause disadherence.
- The tumor cell embolus finds itself within the vascular lumen in the first place because it stimulates a vascular channel to form around it rather than intravasating into a pre-existing lymphatic or capillary. The enveloping vascular channel does not form from angiogenesis but rather from vasculogenesis as evidenced by experiments where tumor cell emboli (IBC spheroids) are admixed with murine embryonal fibroblasts labeled with green fluorescent protein (GFP) and injected into scid mice. Tumor emboli are observed within lymphovascular spaces where the endothelial cells express vasculogenesis markers as well as endothelial markers. These endothelial cells also express GFP, evidence that they must have formed from the injected GFP-labeled murine embryonal fibroblasts.
“Conclusion: The molecular basis of IBC provides a mechanism by which IBC bypasses the traditional steps of intravasation, dissemination and extravasation in its metastatic pathway and affords opportunities for therapeutic intervention.“
