Abstract
Though current pathological methods are greatly improved, they provide rather limited functional information. Cell-in-cell structures (CICs), arising from active cell–cell interaction, are functional surrogates of complicated cell behaviors within heterogeneous cancers. In light of this, we performed the subtype-based CIC profiling in human breast cancers by the “EML” multiplex staining method, and accessed their values as prognostic factors by Cox univariate, multivariate, and nomogram analysis. CICs were detected in cancer specimens but not in normal breast tissues. A total of five types of CICs were identified with one homotypic subtype (91%) and four heterotypic subtypes (9%). Overall CICs (oCICs) significantly associated with patient overall survival (OS) (P = 0.011) as an independent protective factor (HR = 0.423, 95% CI, 0.227–0.785; P = 0.006). Remarkably, three CICs subtypes (TiT, TiM, and MiT) were also independent prognostic factors. Among them, higher TiT, from homotypic cannibalism between tumor cells, predicted longer patient survival (HR = 0.529, 95% CI, 0.288–0.973; P = 0.04) in a way similar to that of oCICs and that (HR = 0.524, 95% CI, 0.286–0.962; P = 0.037) of heterotypic TiM (tumor cell inside macrophage); conversely, the presence of MiT (macrophage inside tumor cell) predicted a death hazard of 2.608 (95% CI, 1.344–5.063; P = 0.05). Moreover, each CIC subtype tended to preferentially affect different categories of breast cancer, with TiT (P < 0.0001) and oCICs (P = 0.008) targeting luminal B (Her2+), TiM (P = 0.011) targeting HR− (Her2+/HR− and TNBC), and MiT targeting luminal A (P = 0.017) and luminal B (Her−) (P = 0.006). Furthermore, nomogram analysis suggested that CICs impacted patient outcomes in contributions comparable (for oCICs, TiT, and TiM), or even superior (for MiT), to TNM stage and breast cancer subtype, and incorporating CICs improved nomogram performance. Together, we propose CICs profiling as a valuable way for prognostic analysis of breast cancer and that CICs and their subtypes, such as MiT, may serve as a type of novel functional markers assisting clinical practices.
Highlights
Breast cancer, like all the other types of human tumors, is highly heterogeneous at both molecular and cellular levels [1, 2] and requires careful subtyping prior to further clinical managements
Cell-in-cell structures (CICs) had been extensively reported in various human tumors for a century [10], this study represents the first systemic analysis of CIC subtypes in human cancers
Our results suggest that subtype-based prognostic analysis is informative and essential as heterogeneous tumors generally give rise to different types of CICs that could impact patient outcomes differently or even oppositely
Summary
Like all the other types of human tumors, is highly heterogeneous at both molecular and cellular levels [1, 2] and requires careful subtyping prior to further clinical managements. We established a multiplex “EML” method [9] to subtype CICs in human cancer tissues, in which samples were simultaneously stained with antibodies against E-cadherin, CD68, and CD45, the markers for epithelial cancer cells, macrophages, and leukocytes, respectively. This method turned out to work well in a small amount of samples from different types of human cancers including breast cancer
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