Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface

Abstract

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness

“…1, the typical median and average LSCC epithelia clusters size in 2D is at least one order of magnitude higher than single cells and tumor buds. Furthermore, studies of the 3D tumor microarchitecture suggest that single cells may be part of tumor buds, which in turn may belong to larger tumor nests or branches (41). Alternatively, current progresses in digital pathology have led to automated identification of prognostic features on histologic sections, notably for NSCLC (42).…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…Epithelial tumors invade collectively, with duct-like patterns and E-cadherin and b-catenin positive cell-cell junctions, with or without lumen formation, and with or without up-regulation of EMT markers, including Twist and Zeb1 (Cheung et al 2013;Bronsert et al 2014). Furthermore, both E-and N-cadherin can orchestrate AJs and cell-cell interactions in cancer cells (Bronsert et al 2014;Zucchini et al 2014).…”

“…In experimental live-cell models, all types of collective movements can be adopted by tumor cells including (1) cohesive sheets or strands, typically detected in epithelial cancers; (2) isolated clusters detached from the primary/metastatic lesion such as epithelial tumors and melanoma; (3) neuronal-like networks of connected cells, detected in neuroectodermal tumors, such as glioblastoma; or (4) as "jammed" collective cohorts induced by spatially narrow tissue boundaries (confinement) of otherwise transiently/loosely connected (single) cells in experimental melanoma and sarcoma models (Friedl et al 1995Nguyen-Ngoc and Ewald 2013). Similarly, histological examination of both patient lesions and mouse models in vivo shows that the collective invasion patterns develop striking morphological and molecular variability, depending on tumor type and the tissue that is invaded (Weigelin et al 2012;Bronsert et al 2014).…”

“…Epithelial tumors invade collectively, with duct-like patterns and E-cadherin and b-catenin positive cell-cell junctions, with or without lumen formation, and with or without up-regulation of EMT markers, including Twist and Zeb1 (Cheung et al 2013;Bronsert et al 2014). Furthermore, both E-and N-cadherin can orchestrate AJs and cell-cell interactions in cancer cells (Bronsert et al 2014;Zucchini et al 2014). Besides cadherins, Ig superfamily members and ephrins/EpH receptor systems were implicated in mediating more labile or transient cell-cell interactions in cancer cells (Cavallaro and Christofori 2004;Haeger et al 2014;Krusche et al 2016).…”

Applied stretch initiates directional invasion via the action of Rap1 GTPase as a tension sensor

“…Tumor cells can invade the local stromal as single cells, but frequently do so by collectively pushing into the matrix as an elongated structure (Bronsert et al, 2014). Collective tumor cell invasion maintains cell-cell adhesion while cells at the invasive front adhere to the ECM.…”