A Dubrovska

C Li

CJ McGinn

CL Chaffer

DJ Rodda

DR Coombe

E Furusawa

F Liu

F Notta

F Yu

H Makita

I Chambers

I Ischenko

J Stutterheim

J Veeraraghavan

J Wen

J Zhou

JI Yang

JM Cates

JP Morris

K He

K Mitsui

KC Chiang

L Vermeulen

LH Long

M Herreros-Villanueva

M Natarajan

M Todaro

MT Mueller

N Aravindan

PC Hermann

PJ Campbell

RG Jayasooriya

RL Zhang

S Aravindan

S Bao

S Nakajima

S Sang

S Yachida

S Yamada

SJ Dylla

T Arumugam

T Tanaka

T Torigoe

TB Hartomo

W Li

X Li

XD Sun

Y Lu

Y Yoshie

YV Yuan

Z Rasheed

Z Wang

English

Abstract
                Introduction
                Therapy-associated onset of stemness-maintenance in surviving tumor-cells dictates tumor relapse/recurrence. Recently, we recognized the anti-pancreatic cancer (PC) potential of seaweed polyphenol manifolds and narrowed down three superior drug-deliverables that could serve as adjuvants and benefit PC cure. Utilizing the PC- cancer stem cells (PC-CSCs) grown ex vivo and mouse model of residual-PC, we investigated the benefits of seaweed polyphenols in regulating stemness-maintenance.
              
                Methods
                ALDH+CD44+CD24+ PC-CSCs from Panc-1, Panc-3.27, MiaPaCa-2, or BxPC-3 cells-derived xenografts grown ex vivo were either mock-irradiated, exposed to fractionated irradiation (FIR, 2Gy/D for 5 days), treated with polyphenols (100 μg/ml) of Hormophysa triquerta (HT-EA), Spatoglossum asperum (SA-EA) or Padina tetrastromatica (PT-EA) with/without FIR were examined for cell viability, transcription of 93 stem-cell-related molecules (QPCR profiling). Polyphenol-dependent regulation of FIR-transactivated Oct4, Zic3, EIF4C, Nanog, and LIF (QPCR) and functional translation of Nanog, SOX2, and OCT3/4 (immunoblotting) were examined in Panc-1/Panc-3.27/MiaPaCa-2/BxPC-3-xenografts derived PC-CSCs. Effect of seaweed-polyphenols in the regulation of EMT (N-Cadherin), pluripotency- (SOX2, OCT3/4, Nanog) and stemness-maintenance (PI3KR1, LIF, CD44) in therapy (FIR, 2Gy/D for 5D/wk for 3-weeks) resistant residual tumors were examined by tissue microarray construction and automated immunohistochemistry.
              
                Results
                Ex vivo exposure of PC-CSCs to SA-EA, PT-EA and HT-EA exhibit dose-dependent inhibition of cell viability. FIR amplified the transcription of 69, 80, 74 and 77 stem-cell related genes in MiaPaCa-2-, Panc-1-, Panc-3.27- and BXPC3-established xenograft-derived ALDH+CD44+CD24+PC-CSCs. Treatment with SA-EA, PT-EA, or HT-EA completely suppressed FIR-activated stem-cell transcriptional machinery in ALDH+CD44+CD24+PC-CSCs established from MiaPaCa-2, Panc-1, Panc-3.27 and BXPC3 xenografts. QPCR validated EIF4C, OCT3/4, Nanog, LIF, and ZIC3 transcriptional profile outcomes. Nanog, Sox2, and OCT3/4 immunoblotting affirmed the PC-CSC radiosensitizing benefit of seaweed polyphenols. Residual-PC tissues microarrayed and immunostained after in vivo treatments recognized complete regulation of FIR-induced SOX2, OCT3/4, Nanog, LIF, CD44, PIK3R1, N-Cadherin, and E-Cadherin with SA-EA, PT-EA, and HT-EA.
              
                Conclusions
                These data, for the first time, documented the EMT/stemness-maintenance in therapy-resistant PC-CSCs. Further, the data suggest that seaweed polyphenols may inhibit PC relapse/recurrence by targeting therapy-orchestrated stem-cell signaling in residual cells.
              </jats:sec

Sheeja Aravindan

Satish Kumar Ramraj

Somasundaram T. Somasundaram

Terence S. Herman

Natarajan Aravindan

Crossref

Stem Cell Research & Therapy

Polyphenols from marine brown algae target radiotherapy-coordinated EMT and stemness-maintenance in residual pancreatic cancer

https://stemcellres.biomedcentral.com/track/pdf/10.1186/s13287-015-0173-3?site=stemcellres.biomedcentral.com

Polyphenols from marine brown algae target radiotherapy-coordinated EMT and stemness-maintenance in residual pancreatic cancer

Abstract

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