Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

Rasmus S Pedersen; Neel I Nissen; Christina Jensen; Jeppe Thorlacius-Ussing; Tina Manon-Jensen; Majken L Olesen; Lasse L Langholm; Hadi M H Diab; Lars N Jorgensen; Carsten P Hansen; Inna M Chen; Julia S Johansen; Morten A Karsdal; Nicholas Willumsen

doi:10.3390/biom12091315

Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

Rasmus S Pedersen^*, Neel I Nissen, Christina Jensen, Jeppe Thorlacius-Ussing, Tina Manon-Jensen, Majken L Olesen, Lasse L Langholm, Hadi M H Diab, Lars N Jorgensen, Carsten P Hansen, Inna M Chen, Julia S Johansen, Morten A Karsdal, Nicholas Willumsen

^*Corresponding author for this work

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1-4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22-5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials.

Original language	English
Article number	1315
Journal	Biomolecules
Volume	12
Issue number	9
ISSN	2218-273X
DOIs	https://doi.org/10.3390/biom12091315
Publication status	Published - 17 Sept 2022

Keywords

Biomarkers/metabolism
Carcinoma, Pancreatic Ductal/metabolism
Collagen Type III
Collagen Type VI
Complement C3
Fibrosis
Humans
Pancreatic Neoplasms/metabolism
Plasma Kallikrein
Prognosis
Transforming Growth Factor beta/metabolism
Tumor Microenvironment

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Pedersen, R. S., Nissen, N. I., Jensen, C., Thorlacius-Ussing, J., Manon-Jensen, T., Olesen, M. L., Langholm, L. L., Diab, H. M. H., Jorgensen, L. N., Hansen, C. P., Chen, I. M., Johansen, J. S., Karsdal, M. A., & Willumsen, N. (2022). Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis. Biomolecules, 12(9), Article 1315. https://doi.org/10.3390/biom12091315

Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis. / Pedersen, Rasmus S; Nissen, Neel I; Jensen, Christina et al.
In: Biomolecules, Vol. 12, No. 9, 1315, 17.09.2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Pedersen, RS, Nissen, NI, Jensen, C, Thorlacius-Ussing, J, Manon-Jensen, T, Olesen, ML, Langholm, LL, Diab, HMH , Jorgensen, LN , Hansen, CP , Chen, IM , Johansen, JS, Karsdal, MA & Willumsen, N 2022, 'Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis', Biomolecules, vol. 12, no. 9, 1315. https://doi.org/10.3390/biom12091315

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title = "Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1-4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22-5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials.",

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author = "Pedersen, {Rasmus S} and Nissen, {Neel I} and Christina Jensen and Jeppe Thorlacius-Ussing and Tina Manon-Jensen and Olesen, {Majken L} and Langholm, {Lasse L} and Diab, {Hadi M H} and Jorgensen, {Lars N} and Hansen, {Carsten P} and Chen, {Inna M} and Johansen, {Julia S} and Karsdal, {Morten A} and Nicholas Willumsen",

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T1 - Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

AU - Pedersen, Rasmus S

AU - Nissen, Neel I

AU - Jensen, Christina

AU - Thorlacius-Ussing, Jeppe

AU - Manon-Jensen, Tina

AU - Olesen, Majken L

AU - Langholm, Lasse L

AU - Diab, Hadi M H

AU - Jorgensen, Lars N

AU - Hansen, Carsten P

AU - Chen, Inna M

AU - Johansen, Julia S

AU - Karsdal, Morten A

AU - Willumsen, Nicholas

PY - 2022/9/17

Y1 - 2022/9/17

N2 - Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1-4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22-5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials.

AB - Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1-4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22-5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials.

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KW - Carcinoma, Pancreatic Ductal/metabolism

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KW - Collagen Type VI

KW - Complement C3

KW - Fibrosis

KW - Humans

KW - Pancreatic Neoplasms/metabolism

KW - Plasma Kallikrein

KW - Prognosis

KW - Transforming Growth Factor beta/metabolism

KW - Tumor Microenvironment

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U2 - 10.3390/biom12091315

DO - 10.3390/biom12091315

M3 - Journal article

C2 - 36139154

SN - 2218-273X

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JO - Biomolecules

JF - Biomolecules

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M1 - 1315

ER -

Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

Abstract

Keywords

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