Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Fibroblast Cell Cultures—Scar-In-A-Jar
2.2. Assessment of Metabolic Cell Viability by Alamar Blue
2.3. Decellularization of Matrix, Sirius Red Staining, and Fibril Orientation Quantification
2.4. Assessment of Collagen Formation in Cell Cultures and Human Serum Samples
2.5. Patients
2.6. Statistical Analysis
3. Results
3.1. Pancreatic CAFs Have Greater Fibrotic Potential Than PFs
3.2. TGF-ß Induces Type III Collagen Formation, but Not Type VI Collagen Formation
3.3. Type III and VI Collagen Production Is Inhibited by ALK5i in CAFs
3.4. Collagen Fibers from CAFs Are More Aligned Than Collagen Fibers Produced by PFs
3.5. PRO-C3 and PRO-C6 Are Prognostic for OS in PDAC—Translational Value of the PDAC SiaJ Model
3.6. High Serum PRO-C3 Levels Are Predictive of Short OS in Patients with PDAC
3.7. High Serum PRO-C6 Levels Are Predictive of Short OS in Patients with PDAC
3.8. Combination PRO-C3 and PRO-C6 Are Complementary
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Variables (PDAC) | Study Population (n = 810) |
---|---|
Age, (years) | |
Median (min, max) | 66 (37–89) |
Gender, n (%) | |
Male | 433 (53%) |
Female | 377 (47%) |
Number of metastatic sites, n (%) | |
0 site | 376 (46%) |
≥1 site | 434 (54%) |
Liver metastasis (of all patients with metastasis, n = 434), n (%) | |
Yes | 331 (76%) |
No | 103 (24%) |
BMI | |
Median (min, max) | 23 (14–39) |
Stage | |
1 | 15 (2%) |
2 | 123 (15%) |
3 | 237 (29%) |
4 | 431 (53%) |
Unknown | 4 (<1 %) |
Diabetes | |
Yes | 198 (24%) |
No | 603 (74%) |
Unknown | 9 (1%) |
Tobacco | |
Ever | 484 (60%) |
Never | 251 (31%) |
Unknown | 75 (9%) |
Alcohol | |
<DHAR | 554 (68%) |
>DHAR | 179 (22%) |
Unknown | 77 (10%) |
CA19-9 (U/mL) | |
≤median (≤506 U/mL) | 395 (49%) |
>median (>506 U/mL) | 387 (48%) |
Unknown | 28 (3%) |
Performance status, n (%) | |
0 | 294 (36%) |
1 | 335 (41%) |
2 | 89 (11%) |
3 | 5 (<1%) |
Unknown | 87 (11%) |
The Charlson age comorbidity index | |
<4 | 538 (66%) |
≥4 | 258 (32%) |
Unknown | 14 (2%) |
Table 2: Uni- and Multivariate Analysis (Overall Survival), n = 810 | Univariate | Multivariate | Multivariate * Kombi | ||||
---|---|---|---|---|---|---|---|
Variables | HR (95% Cl) | p-Value | HR (95% Cl) | p-Value | HR (95% Cl) | p-Value | |
PRO-C3 | Continuous | 1.00 (1.00–1.00) | 0.0036 | - | - | - | - |
>median vs. ≤median | 1.48 (1.29–1.71) | <0.0001 | 1.24 (1.04–1.47) | 0.0149 | - | - | |
PRO-C6 | Continuous | 1.05 (1.03–1.07) | <0.0001 | - | - | - | - |
>median vs. ≤median | 1.31 (1.14–1.50) | 0.0002 | 1.15 (0.97–1.36) | 0.1139 | - | - | |
PRO-C3 and PRO-C6 | High + high vs. low + lowLow + high or high + low vs. low + low | 1.60 (1.35–1.90) 1.33 (1.12–1.58) | <0.0001 0.0014 | - | - | 1.42 (1.18–1.71) 1.19 (0.99–1.43) | 0.0002 0.0703 |
Age | Per year increase | 1.01 (1.00–1.02) | 0.0199 | 1.01 (1.00–1.36) | 0.1694 | 1.01 (1.00–1.02) | 0.1916 |
Gender | Female vs. male | 0.97 (0.85–1.12) | 0.7063 | - | - | - | - |
Number of metastatic sites | ≥1 vs. 0 | 2.56 (2.21–2.97) | <0.0001 | 1.52 (1.18–2.00) | 0.0011 | 1.51 (1.18–1.95) | 0.0013 |
Liver metastasis | Yes vs. no | 2.37 (2.05–2.75) | <0.0001 | 1.28 (1.01–1.62) | 0.0396 | 1.28 (1.02–1.63) | 0.0363 |
BMI | Continuous | 0.99 (0.97–1.01) | 0.2344 | - | - | - | - |
Stage | 3 + 4 vs. 1 + 2 | 2.85 (2.33–3.50) | <0.0001 | 1.97 (1.52–2.55) | <0.0001 | 1.97 (1.52–2.56) | <0.0001 |
Diabetes | Yes vs. no | 1.08 (0.92–1.27) | 0.3431 | - | - | - | - |
Tobacco | Ever vs. never | 1.06 (0.91–1.24) | 0.4448 | - | - | - | - |
Alcohol | >DHAR vs. <DHAR | 1.05 (0.88–1.24) | 0.6112 | - | - | - | - |
CA19-9 | >median vs. ≤ median | 2.01 (1.69–2.39) | <0.0001 | 1.53 (1.30–1.80) | <0.0001 | 1.54 (1.23–1.70) | <0.0001 |
PS | 1 + 2+3 vs. 0 | 1.58 (1.36–1.85) | <0.0001 | 1.45 (1.24–1.71) | <0.0001 | 1.44 (1.23–1.69) | <0.0001 |
CACI | High (≥4 vs. <4) | 1.14 (0.98–1.33) | 0.0860 | - | - | - | - |
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Nissen, N.I.; Johansen, A.Z.; Chen, I.; Johansen, J.S.; Pedersen, R.S.; Hansen, C.P.; Karsdal, M.A.; Willumsen, N. Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma. Cancers 2022, 14, 819. https://doi.org/10.3390/cancers14030819
Nissen NI, Johansen AZ, Chen I, Johansen JS, Pedersen RS, Hansen CP, Karsdal MA, Willumsen N. Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma. Cancers. 2022; 14(3):819. https://doi.org/10.3390/cancers14030819
Chicago/Turabian StyleNissen, Neel I., Astrid Z. Johansen, Inna Chen, Julia S. Johansen, Rasmus S. Pedersen, Carsten P. Hansen, Morten A. Karsdal, and Nicholas Willumsen. 2022. "Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma" Cancers 14, no. 3: 819. https://doi.org/10.3390/cancers14030819