Vasculogenic mimicry plays an important role in adrenocortical carcinoma

Abstract

Abbreviations & Acronyms ACC = adrenocortical carcinoma CCK-8 = Cell Counting Kit-8 OS = overall survival PAS = periodic acid-Schiff PBS = phosphate-buffered saline qPCR = quantitative polymerase chain reaction siRNA = small interfering ribonucleic acid TKI = tyrosine kinase inhibitor VEGF = vascular endothelial growth factor VEGFR-2 = vascular endothelial growth factor receptor 2 VM = vasculogenic mimicry Objectives: To determine the prognostic role of vasculogenic mimicry in adrenocortical carcinoma, and to explore its relationship with vascular endothelial growth factor receptor 2 expression. Methods: A total of 46 samples of adrenocortical carcinoma were collected and reviewed. Vasculogenic mimicry and vascular endothelial growth factor receptor 2 were detected by immunohistochemistry and double staining. Survival analysis was carried out to access pronostic significance. Three-dimensional culture method was applied to test the ability of vasculogenic mimicry formation by adrenocortical carcinoma cell lines SW-13 and H295R. Quantitative polymerase chain reaction and western blotting were used to monitor the expression of vascular endothelial growth factor receptor 2 in SW-13 and H295R. After being treated with specific inhibitor or small interfering ribonucleic acid to downregulate expression of vascular endothelial growth factor receptor 2, vasculogenic mimicry formation and cell prolifration of SW-13 cells were evaluated by 3-D culture and Cell Counting Kit-8 methods. Results: Vasculogenic mimicry was observed in 19 of the 46 (41.30%) adrenocortical carcinoma samples. Both vasculogenic mimicry and vascular endothelial growth factor receptor 2 expressions showed a positive association with Weiss score and TNM stage, whereas vascular endothelial growth factor receptor 2 was also associated with tumor size (all P < 0.05). Vasculogenic mimicry was closely correlated with vascular endothelial growth factor receptor 2 expressions (r = 0.470, P < 0.01). The median overall survival of patients with vasculogenicmimicry-positive or vascular endothelial growth factor receptor 2-positive was shorter than that of patients with vasculogenic mimicry-negative or vascular endothelial growth factor receptor 2-negative (P = 0.001 and 0.028, respectively). The vasculogenic mimicry-forming SW-13 cells expressed higher levels of vascular endothelial growth factor receptor 2 than that of H295R, which was unable to form vasculogenic mimicry on Matrigel. However, downregulation of vascular endothelial growth factor receptor 2 only decreased cell proliferation, but not vasculogenic mimicry formation by SW-13 cells. Conclusions: Vasculogenic mimicry and overexpression of vascular endothelial growth factor receptor 2 seem to correlate with poor prognostic outcomes in adrenocortical carcinoma. Anti-angiogenesis treatments targeting vascular endothelial growth factor receptor 2 should be combined with therapies targeting vasculogenic mimicry in adrenocortical carcinoma.

Fact or Fiction, It Is Time for a Verdict on Vasculogenic Mimicry?

“…Strikingly, reports in ovarian and colorectal cancers classified as VM+ showed lower survival time in the magnitude of years compared to VM- tumors (30, 31). Similar differences were observed in orbital rhabdomyosarcoma and adrenocorticoid carcinomas (32, 33). Gastric cancer patients with PAS+ structures were prone to present higher histological grade, metastasis, distant recurrence, and 12 months less cumulative OS (34).…”

Three Dimensional Cell Culturing for Modeling Adrenal and Pituitary Tumors

“…Interestingly, in several tumor types 3D models have been introduced into research modalities however they are lacking regarding endocrine tumor types. To date, four of each adrenocortical carcinoma, pituitary neuroendocrine tumor (pitNET) and pheochromocytoma [9][10][11][12][13][14][15][16][17][18][19][20] reports have been published using 3D cultures, they are different in terms of the applied methods and no viability and lifespan analysis have been tested and compared among different culture conditions. Therefore, in the use of 3D culturing in routine research applications the methodology should be optimized and standardized in order to maintain viability observed in vivo systems.…”

TM4SF5 promotes metastatic behavior of cells in 3D extracellular matrix gels by reducing dependency on environmental cues

“…TM4SF5-expressing epithelial cancer cells appeared to have angiogenic or vasculogenic properties; for examples, under 2D conditions, they formed a network-like growth pattern, and in 3D gels made of Matrigel and collagen I, they displayed endothelial-like networks with VE-cadherin mRNA and protein expression. Vasculogenic mimicry is clinically well-known to indicate its high metastatic potential [ 23 – 25 ]. The angiogenic and vasculogenic transformation mechanisms of TM4SF5-positive cancer cells need further exploration.…”