Transcriptomic Profile of Lymphovascular Invasion, a Known Risk Factor of Pancreatic Ductal Adenocarcinoma Metastasis

Abstract

Lymphovascular invasion (LVI) is an aggressive pathologic feature and considered a risk factor for distant metastasis. We hypothesized that pancreatic ductal adenocarcinomas (PDACs) with LVI are associated with shorter survival, as well as aggressive cancer biology and lymphangiogenesis in transcriptomic analysis. Utilizing the cancer genome atlas (TCGA)-PDAC cohort, we found that positive LVI was significantly associated with positive perineural invasion (PNI) (p = 0.023), and higher American Joint Committee on Cancer (AJCC) T (p = 0.017) and N (p < 0.001) categories. Furthermore, positive LVI was associated with shorter overall survival (OS) (p = 0.014) and was an independent risk factor of poor OS. Although there was no association between LVI status and lymphangiogenesis, epithelial-mesenchymal transition (EMT), or metastasis-related genes, Gene Set Enrichment Analysis revealed a strong association with cell-proliferation-related gene sets such as mitotic spindles (Normalized enrichment score (NES) = 1.76, p = 0.016) and G2/M checkpoints (NES = 1.75, p = 0.036), as well as with transforming growth factor beta (TGF-beta) signaling (NES = 1.61, p = 0.043), which is a known mechanism of metastasis in PDACs. In conclusion, positive LVI was an independent risk factor of poor OS in PDACs. We found that PDACs with LVI were possibly associated with accelerated cell proliferation and enhanced TGF-beta signaling independent of lymphangiogenesis. Transcriptomic profiling elucidates more precise tumor biology of LVI-positive PDACs.

Annexin A1 Expression Is Associated with Epithelial–Mesenchymal Transition (EMT), Cell Proliferation, Prognosis, and Drug Response in Pancreatic Cancer

“…Yamazaki et al reported that epithelial–mesenchymal transition (EMT) activity in PC is a promising prognostic biomarker. Our group reported that high activity of the G2M checkpoint pathway [ 5 ] and lympho-vascular invasion [ 6 ] is associated with worse survival. In contrast, the abundance of mature blood vessels [ 7 ] and fibroblasts in PC [ 8 ] is associated with better survival.…”

Prognostic Significance of Microvascular Invasion in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis

“…The characteristics of the 17 studies with a total of 7427 patients are summarized in Table 1 [ 7 – 12 , 14 , 15 , 17 , 20 – 24 , 28 – 30 ]. All articles were retrospective and observational studies, 4 of which were from China, 6 were from the USA, 3 were from Japan, and the others were from Italy, South Korea, and France.…”

“…We identified 17 reports of retrospective studies that described the incidence of MVI in PDAC cases ( Figure 2 ) [ 7 – 12 , 14 , 15 , 17 , 20 – 24 , 28 – 30 ]. Thesestudies evaluated 7427 cases of PDAC, including 4029 cases with MVI.…”

“…MVI mostly describes microvessel invasion [ 18 ], while LVI is used to indicate micro-lymph-tubule invasion [ 19 ]. However, in the literature reviewed, only a few studies distinguished the 2 terms [ 9 , 15 ]; in most cases, they refer to the same pathological characteristics [ 7 , 11 , 12 , 14 , 20 – 23 ], which leads to confusion. In addition, the incidence of MVI in PDAC varies considerably [ 7 – 12 , 14 , 15 , 20 – 24 ] and the literature rarely discusses the potential mechanism of MVI in the progression of PDAC, so the mechanism and clinical significance of MVI in poor PDAC outcomes remains incompletely understood.…”

“…However, in the literature reviewed, only a few studies distinguished the 2 terms [ 9 , 15 ]; in most cases, they refer to the same pathological characteristics [ 7 , 11 , 12 , 14 , 20 – 23 ], which leads to confusion. In addition, the incidence of MVI in PDAC varies considerably [ 7 – 12 , 14 , 15 , 20 – 24 ] and the literature rarely discusses the potential mechanism of MVI in the progression of PDAC, so the mechanism and clinical significance of MVI in poor PDAC outcomes remains incompletely understood. We therefore conducted a systematic review and meta-analysis of all observational studies to examine the incidence, definition, clinical significance, and potential mechanism of MVI in PDAC, to help guide more personalized and effective preoperative or postoperative strategies to achieve better survival outcomes in patients with PC.…”