Geometric Tumor Embolic Budding Characterizes Inflammatory Breast Cancer

Abstract

Background The sina qua non of IBC is numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. Methods In observational human studies comparing IBC with non-IBC, although common tumor parameters such as Ki-67 index, mitotic count and nuclear size showed a reasonable overlap, there was a dramatic exponential or geometric difference in embolic density and a significant difference in embolic size distribution in IBC v non-IBC. In companion experimental studies using contrasting properties of two xenografts, Mary-X and Karen-X, both derived from IBC patients, this study offers a novel explanation and mechanism to explain the high tumor embolic numbers in IBC. Results The explanation is geometric embolic budding. Mary-X exhibits florid lymphovascular tumor emboli in vivo which give rise to high numbers of CTCs and pulmonary metastases whereas Karen-X lacks these features. Mary-X also gives rise to tight spheroids in vitro which exhibit dynamic budding whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into daughter emboli in vivo. The mechanism that regulates the compactness of the spheroids as well as the emboli involves the generation of E-cad/NTF1, a calpain-mediated cleavage product of membrane E-cadherin. Inhibiting the generation of E-cad/NFT1 by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides both reduces spheroid compactness and decreases budding. Conclusions Since E-cad/NFT1 retains the p120ctn binding site but loses both the β-catenin and α-binding sites, promoting its 360° distribution around the cell’s membrane, the varying levels of expression of this truncated molecule may trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of tumor emboli seen in IBC patients.