Inherent phenotypic plasticity facilitates progression of head and neck cancer: Endotheliod characteristics enable angiogenesis and invasion

Abstract

The presence of the EMT (epithelial-mesenchymal transition), EndMT (endothelial-mesenchymal transition) and VM (vasculogenic mimicry) demonstrates the multidirectional extent of phenotypic plasticity in cancers. Previous findings demonstrating the crosstalk between head and neck squamous cell carcinoma (HNSCC) and vascular endothelial growth factor (VEGF) imply that HNSCC cells share some functional commonalities with endothelial cells. Our current results reveal that cultured HNSCC cells not only possess endothelial-specific markers, but also display endotheliod functional features including low density lipoprotein uptake, formation of tube-like structures on Matrigel and growth state responsiveness to VEGF and endostatin. HNSCC cell subpopulations are also highly responsive to transforming growth factor-β1 and express its auxiliary receptor, endoglin. Furthermore, the endotheliod characteristics observed in vitro recapitulate phenotypic features observed in human HNSCC tumors. Conversely, cultured normal human oral keratinocytes and intact or ulcerated human oral epithelia do not express comparable endotheliod characteristics, which imply that assumption of endotheliod features is restricted to transformed keratinocytes. In addition, this phenotypic state reciprocity facilitates HNSCC progression by increasing production of factors that are concurrently pro-proliferative and pro-angiogenic, conserving cell energy stores by LDL internalization and enhancing cell mobility. Finally, recognition of this endotheliod phenotypic transition provides a solid rationale to evaluate the antitumorigenic potential of therapeutic agents formerly regarded as exclusively angiostatic in scope.

Fenretinide Perturbs Focal Adhesion Kinase in Premalignant and Malignant Human Oral Keratinocytes. Fenretinide's Chemopreventive Mechanisms Include ECM Interactions

“…Similar to our previous ATCC OSCC cell characterization studies [17], JSCC1, JSCC2 and JSCC3 cell cultures uniformly demonstrated strong cytokeratin staining along with coexpression of cytokeratin and vimentin in cellular subpopulations (Supplemental Figure S1). …”

“…Formalin fixed cells were incubated with vimentin (1:200, Abcam, Cambridge, MA) or a pancytokeratin cocktail (AE1/AE3 + 5D3, 1:100, Abcam,) antibodies, followed by incubation with FITC or Texas Red conjugated secondary antibodies (Abcam, Cambridge, MA) [17]. Nuclei were stained with 4′,6′-Diaminidino-2-phenylindole dihydrochloride (DAPI, Abcam).…”

Vasculogenic Mimicry: A Promising Prognosticator in Head and Neck Squamous Cell Carcinoma and Esophageal Cancer? A Systematic Review and Meta-Analysis

“…Hypoxia was also reported to promote VM through other signaling pathways, such as the extravascular VE-cadherin and its role in the acquisition of the VM phenotype [46]. In addition, the multi-phenotypic reciprocity, observed in VM-forming cancer cells, has the capacity to facilitate tumor progression and metastasis [47,48]. Because of such a phenotypic switch, the VM-forming ELC are different from normal endothelial cells, rendering the VM channels inherently resistant to conventional anti-angiogenic therapy [32,49].…”

Overview of advances in vasculogenic mimicry – a potential target for tumor therapy

“…Additionally, tumor cell mobility and invasiveness were heightened. 34 In non–small cell lung cancer, Dickkopf-1 significantly induces VM formation and promotes cancer cell growth, migration, and metastasis via overexpression of EMT- and CSC-associated proteins. 35 Maspin has a positive correlation with VM; deregulated maspin facilitates tumor cell invasion and metastasis in non–small cell lung cancer.…”