Clinically relevant morphological structures in breast cancer represent transcriptionally distinct tumor cell populations with varied degrees of epithelial-mesenchymal transition and CD44+CD24- stemness

Abstract

Intratumor morphological heterogeneity in breast cancer is represented by different morphological structures (tubular, alveolar, solid, trabecular, and discrete) and contributes to poor prognosis; however, the mechanisms involved remain unclear. In this study, we performed 3D imaging, laser microdissection-assisted array comparative genomic hybridization and gene expression microarray analysis of different morphological structures and examined their association with the standard immunohistochemistry scorings and CD44+CD24- cancer stem cells. We found that the intratumor morphological heterogeneity is not associated with chromosomal aberrations. By contrast, morphological structures were characterized by specific gene expression profiles and signaling pathways and significantly differed in progesterone receptor and Ki-67 expression. Most importantly, we observed significant differences between structures in the number of expressed genes of the epithelial and mesenchymal phenotypes and the association with cancer invasion pathways. Tubular (tube-shaped) and alveolar (spheroid-shaped) structures were transcriptionally similar and demonstrated co-expression of epithelial and mesenchymal markers. Solid (large shapeless) structures retained epithelial features but demonstrated an increase in mesenchymal traits and collective cell migration hallmarks. Mesenchymal genes and cancer invasion pathways, as well as Ki-67 expression, were enriched in trabecular (one/two rows of tumor cells) and discrete groups (single cells and/or arrangements of 2-5 cells). Surprisingly, the number of CD44+CD24- cells was found to be the lowest in discrete groups and the highest in alveolar and solid structures. Overall, our findings indicate the association of intratumor morphological heterogeneity in breast cancer with the epithelial-mesenchymal transition and CD44+CD24- stemness and the appeal of this heterogeneity as a model for the study of cancer invasion.

Different Morphological Structures of Breast Tumors Demonstrate Individual Drug Resistance Gene Expression Profiles

“…Previously, we found that genes encoding ABC transporters are differentially expressed between various morphological structures [4]. Our resent study showed that different morphological structures represent transcriptionally distinct populations of tumor cells with varying degrees of epithelialmesenchymal transition and stemness [5]. Based on these results, we assumed that various morphological structures carry specific characteristics which modify chemotherapy efficiency.…”

“…1, b, c). In addition, the highly heterogeneous composition of these morphological structures [5] may contribute to drug resistance and should be considered when an appropriate chemotherapy regimen is chosen.…”

“…Transcriptome profiling was performed using the SurePrint G3 Human GE v2, 8×60K microarrays (Agilent, USA), scanning -using a SureScan Microarray Scanner (Agilent, USA). All procedures were performed as previously described [5]. The microarray data is available in the Gene Expression Omnibus (GEO, GSE80754).…”

Macrophages and tumor progression: on the way to macrophage-specific therapy

“…В совместных исследованиях сотрудников НИИ онкологии Томского НИМЦ показаны различия характера распределения и фенотипического состава клеток воспалительного инфильтрата вокруг разных морфологических структур опухоли молочной железы. Морфологические структуры на основании их генетической и ýкспрессионной разнородности, установленной авторами, рассматриваются как функционально обособленные популяции опухолевых клеток, обладающих разным метастатическим потенциалом, в обеспечение которого очевидно могут вносить вклад и компоненты микроокружения [67][68][69][70].…”

Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis

“…Previously, we showed that breast tumor cells can be either single, arranged in small (discrete) groups, or arranged in more complex structures (tubular, alveolar, solid, and trabecular) (6). In addition, we suggested that the intratumor morphological heterogeneity in breast cancer is a result of the unfolding of the invasion program during which epithelial-mesenchymal transition (EMT) leads to significant morphogenetic changes in the tumor landscape: from tubular structures that are close to normal mammary ducts to discrete groups of tumor cells demonstrating a strongly pronounced mesenchymal phenotype (7). The recent study hypothesized that the intratumor morphological heterogeneity can be an attractive model for studying the mechanisms of collective cell invasion (by focusing on solid and trabecular structures) and individual cell invasion (by focusing on discrete groups, namely, STCs) (8).…”