Geometric tumor embolic budding characterizes inflammatory breast cancer

Abstract

Purpose Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. Methods This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC’s sina qua non signature of florid lymphovascular emboli. Results In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding. Conclusion Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and β-catenin sites, promoting its 360° distribution around the cell’s membrane, the vacilating levels of this molecule 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 emboli seen in IBC. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-022-06819-6.

Prognostic significance and value of further classification of lymphovascular invasion in invasive breast cancer: a retrospective observational study

“…Tumor-associated angiogenesis is one of the mechanisms that contribute to the high degree of invasiveness of breast cancer as it advances. According to Modi et al [ 25 ], there is an important connection between inflammatory breast cancer and the dermal vasculature. They also proposed that the extent of dermal vascular involvement be clarified.…”

Prognostic significance and value of further classification of lymphovascular invasion in invasive breast cancer: a retrospective observational study

“…Tumor-associated angiogenesis is one of the mechanisms that contribute to the high degree of invasiveness of breast cancer as it advances. According to Modi et al [25], there is an important connection between in ammatory breast cancer and the dermal vasculature. They also proposed that the extent of dermal vascular involvement be clari ed.…”

Updates on Lymphovascular Invasion in Breast Cancer

“…Cutaneous LVI is particularly relevant due to its strict association with the clinical entity of inflammatory breast carcinoma [ 3 ]. Histologic criteria for cutaneous LVI are the same as previously discussed.…”

“…These latter factors cause a substantial phenotypic switch in carcinoma cells triggered by cytoskeletal remodeling, increased expression of degradation protease, inhibiting cell-cell junctions, and cell polarity, which favor cell dissociation, mobility, and tumor invasion [ 41 , 42 ]. Indeed, EMT is a dynamic process where mesenchymal and epithelial features coexist and enable cancer cells to migrate in clusters rather than individually [ 3 , 41 , 43 ]. In fact, LVI typically appears as emboli or cell clusters on histologic examination.…”

“…Moreover, there are site-specific differences in LVI reporting, in particular with regard to the distinction between lymphatic and blood vessel invasion and the size of invaded vessels. In breast cancer (BC), it is not necessary to distinguish blood capillaries from lymphatic channels, but specifying the involvement of dermal vessels is suggested due to its close association with inflammatory breast carcinoma [ 3 , 4 ]. According to the St. Gallen International Expert Consensus Conference guidelines, it is also advised to specify the presence of “extensive” LVI, but the morphological criteria for its consistent definition are still equivocal [ 5 ].…”