Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer.

dc.contributor.author

Kakarla, Mamatha

dc.contributor.author

ChallaSivaKanaka, Sathyavathi

dc.contributor.author

Dufficy, Mary F

dc.contributor.author

Gil, Victoria

dc.contributor.author

Filipovich, Yana

dc.contributor.author

Vickman, Renee

dc.contributor.author

Crawford, Susan E

dc.contributor.author

Hayward, Simon W

dc.contributor.author

Franco, Omar E

dc.date.accessioned

2023-05-03T19:32:45Z

dc.date.available

2023-05-03T19:32:45Z

dc.date.issued

2022-05

dc.date.updated

2023-05-03T19:32:42Z

dc.description.abstract

Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.

dc.identifier

cancers14092336

dc.identifier.issn

2072-6694

dc.identifier.issn

2072-6694

dc.identifier.uri

https://hdl.handle.net/10161/27335

dc.language

eng

dc.publisher

MDPI AG

dc.relation.ispartof

Cancers

dc.relation.isversionof

10.3390/cancers14092336

dc.subject

EFNB1

dc.subject

EFNB2

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EFNB3

dc.subject

Ephrins

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Src family kinases

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Tenascin-C

dc.subject

carcinoma-associated fibroblasts (CAF)

dc.subject

cytokines

dc.subject

paracrine signaling

dc.subject

prostate cancer

dc.subject

reverse signaling

dc.subject

stroma

dc.subject

tumor microenvironment (TME)

dc.title

Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer.

dc.type

Journal article

pubs.begin-page

2336

pubs.issue

9

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Pathology

pubs.publication-status

Published

pubs.volume

14

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