Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Abstract

Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.

The role of thrombomodulin in modulating ITGB3 expression and its implications for triple‐negative breast cancer progression

“…Carcinogenesis and metastasis take place through specific interactions of the tumor cells and the surrounding microenvironment (Baghy, 2016). Integrins are transmembrane receptors and mainly function in facilitating cell‐extracellular matrix (ECM) adhesion (Harryman et al, 2022; Hynes, 1992). Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane (Giancotti & Ruoslahti, 1999; Sökeland & Schumacher, 2019).…”

“…Carcinogenesis and metastasis take place through specific interactions of the tumor cells and the surrounding microenvironment (Baghy, 2016). Integrins are transmembrane receptors and mainly function in facilitating cell-extracellular matrix (ECM) adhesion (Harryman et al, 2022;Hynes, 1992). Upon ligand binding, in TNBC cells (Figure 4a).…”

Phenotype plasticity and altered sensitivity to chemotherapeutic agents in aggressive prostate cancer cells

“…Now, some studies suggest HDAC inhibitors may increase an epithelial-to-mesenchymal (EMT) phenotype transition in PCa treatment (Kong et al, 2012) while others suggest a change in the mesenchymal-to-epithelial transition (MET) phenotype (Wang et al, 2015). Since muscle invasive PCa is a heterogenous population of epithelial cells, with different tumor cell phenotypes appearing as a unit of epithelial-to-mesenchymal cooperation (Harryman et al, 2022), the success of HDACs as therapeutic agents may rely on understanding these complex tumor phenotypes and iHDAC mechanisms (McClure et al, 2018). This point is underscored by recent work reporting transcriptomic remodeling occurring during PCa progression as detected by single cell sequencing (Chen et al, 2021) and the persistence of specialized phenotypes associated with recurrent disease (Taavitsainen et al, 2021).…”

“…DU145 WT tumor cells are an epithelial population of human PCa cells with heterogeneous adhesion properties (Pollan et al, 2021). In a xenograft mouse model, DU145 WT cells will form tumors, seed onto the inferior surface of the smooth muscle diaphragm, and invade into the diaphragm muscle of the animal but will not metastasize (Harryman et al, 2022). Therefore, after IP injection and 5 weeks of incubation in the mouse, DU145 WT tumor cells that had invaded and migrated through the inferior smooth muscle diaphragm of the mouse to reach the superior surface were collected and passaged again in vivo (schematized, Figure 1A).…”

Spatial heterogeneity in tumor adhesion qualifies collective cell migration

“…Epigenetic downregulation of E-cadherin driven by the microenvironment may also result in a variegated expression of the protein in ductal breast cancers [9]. Heterogeneity has also been observed experimentally for receptors such as integrins, which mediate adhesion with ECM [10], [11]. Such variation in spatial expression of adhesive proteins suggests concurrent heterogeneity in the force of inter-cellular and cell-ECM adhesion and can be associated with patient survival as well [12].…”