Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Tumor Patterns
2.2. Study Series
2.3. Cancer-Cell and Stromal Features
2.3.1. Cancer-Cell Features
2.3.2. Stromal Features
2.4. Multiple Patterns within a Single Tumor
2.5. Prediction of Morphological Pattern
3. Discussion
4. Materials and Methods
4.1. Tissues
4.2. Cancer Cell and Stromal Features
4.3. Histochemistry and Immunohistochemistry
4.4. Semiquantitative Scoring
4.5. Quantitative Assessment
4.6. Network Visualization
4.7. Statistical Analysis
4.8. Prediction of Morphological Pattern
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALDH1 | Aldehyde dehydrogenase 1 |
αSMA | α-Smooth muscle actin |
CAF | Cancer-associated fibroblast |
CAV1 | Caveolin-1 |
Col | Collagen |
CP | Chickenwire pattern |
CSC | Cancer stem cell |
ECM | Extracellular matrix |
EMT | Epithelial-mesenchymal transition |
ERT | Extremely randomized tree |
FN | Fibronectin |
FP | Fascicular pattern |
HA | Hyaluronan |
H&E | Hematoxylin and eosin |
IRS | Immunoreactive score |
ITG | Integrin |
MMP14 | Matrix metalloproteinase 14 |
NOS | Not otherwise specified |
PC | Pancreatic cancer |
PCC | Pancreatic cancer cell |
PP | Periglandular pattern |
ROI | Region of interest |
SS | Staining score |
TP | Tendon-like pattern |
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Feature | Experimental Observations | Clinical Relevance |
---|---|---|
ALDH1 |
|
|
αSMA |
| |
CAV1 |
| |
CD44 |
| |
CD133 | ||
Col I |
| |
Col III |
| |
FN |
| |
HA |
| |
ITGα2β1 |
|
|
ITGα5β1 |
| |
MMP14 |
|
Feature | Compart-ment | Kruskal-Wallis Test | Mann–Whitney U Test | |||||
---|---|---|---|---|---|---|---|---|
PP vs. TP | PP vs. FP | PP vs. CP | TP vs. FP | TP vs. CP | FP vs. CP | |||
ALDH1 | C | <0.001 | <0.001 | NS | NS | <0.001 | <0.001 | NS |
αSMA | S | <0.001 | <0.001 | 0.01 | <0.001 | <0.001 | 0.02 | <0.001 |
CAV1 | C | <0.001 | NS | NS | <0.001 | NS | <0.001 | <0.001 |
CAV1 | S | <0.001 | <0.001 | 0.006 | <0.001 | NS | <0.001 | <0.001 |
CD133 | C | <0.001 | <0.001 | NS | <0.001 | <0.001 | NS | <0.001 |
CD44 | C | 0.004 | 0.003 | 0.007 | 0.001 | NS | NS | NS |
Col align | S | 0.001 | 0.001 | 0.011 | 0.001 | <0.001 | <0.001 | NS |
Col I | S | <0.001 | 0.033 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
Col I pattern | S | <0.001 | <0.001 | <0.001 | <0.001 | NS | <0.001 | <0.001 |
Col III | S | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
Col III pattern | S | <0.001 | <0.001 | <0.001 | <0.001 | NS | <0.001 | <0.001 |
Ep prox prox | S | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
FN | S | <0.001 | <0.001 | 0.02 | <0.001 | <0.001 | <0.001 | <0.001 |
FN pattern | S | <0.001 | <0.001 | <0.001 | 0.009 | <0.001 | <0.001 | <0.001 |
HA | S | <0.001 | <0.001 | 0.002 | <0.001 | <0.001 | NS | <0.001 |
ITGα2 | C | <0.001 | <0.001 | 0.001 | <0.001 | NS | NS | NS |
ITGα2 | S | <0.001 | 0.002 | NS | <0.001 | 0.022 | NS | 0.002 |
ITGα5 | S | <0.001 | <0.001 | NS | <0.001 | <0.001 | <0.001 | <0.001 |
ITGα5 pattern | S | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
ITGβ1 | C | <0.001 | <0.001 | <0.001 | <0.001 | NS | <0.001 | <0.001 |
ITGβ1 | S | <0.001 | <0.001 | NS | <0.001 | <0.001 | NS | <0.001 |
Ki67 | C | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
MMP14 | C | <0.001 | 0.001 | <0.001 | 0.037 | <0.001 | <0.001 | <0.001 |
MMP14 | S | <0.001 | <0.001 | <0.001 | NS | <0.001 | <0.001 | <0.001 |
Stromal cell density | S | <0.001 | <0.001 | 0.008 | <0.001 | <0.001 | <0.001 | <0.001 |
Total collagen | S | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | NS |
Tumor Pattern | αSMA (Staining Score) | Total Collagen (Area Fraction %) | Activated Stroma Index | Stromal Subtype |
---|---|---|---|---|
Periglandular | High (2.60) | High (16.95) | 0.27 | Inert |
Tendon-like | Low (1.50) | High (33.21) | 0.05 | Fibrogenic |
Fascicular | High (2.90) | Low (7.35) | 1.35 | Fibrolytic |
Chickenwire | Low (1.20) | Low (3.60) | 0.56 | Dormant |
Immunohistochemical Staining | |||||||
---|---|---|---|---|---|---|---|
Primary Antibodies | |||||||
Antigen | Company | Cat # | Antigen Retrieval | Dilution | Incubation | Species | Control Tissue |
αSMA | Abcam | ab5694 | CB, 100 °C | 1:100 | ON, 4 °C | Rabbit | Blood vessel |
ALDH1A1 | Abcam | ab52492 | CB, 100 °C | 1:800 | ON, 4 °C | Rabbit | Kidney, lung |
Caveolin-1 | Abcam | ab32577 | CB, 100 °C | 1:750 | ON, 4 °C | Rabbit | Liver, lung |
CD133/1 | Miltenyi Biotec | 130–108-062 | CB, 100 °C | 1:100 | ON, 4 °C | Mouse | Gallbladder |
CD44 | Dako | M7082 | CB, 100 °C | 1:200 | ON, 4 °C | Mouse | Gallbladder |
Col Iα1 | LifeSpan BioSciences | LS-B5932 | CB, 100 °C | 1:200 | ON, 4 °C | Mouse | Prostate |
Col III | Abcam | ab7778 | CB, 100 °C | 1:300 | ON, 4 °C | Rabbit | Testis |
Fibronectin | Abcam | ab6328 | TEB, 100 °C | 1:300 | ON, 4 °C | Mouse | Granulation tissue |
ITGα2 | Abcam | ab133557 | CB, 100 °C | 1:1000 | ON, 4 °C | Rabbit | Testis |
ITGα5 | Abcam | ab150361 | CB, 100 °C | 1:200 | ON, 4 °C | Rabbit | Placenta |
ITGβ1 | ThermoFisher | MA5-17103 | CB, 100 °C | 1:200 | ON, 4 °C | Mouse | Small intestine |
Ki67 | Dako | M7240 | CB, 100 °C | 1:1000 | ON, 4 °C | Mouse | Small intestine |
MMP14 | Abcam | ab51074 | TEB, 100 °C | 1:1600 | ON, 4 °C | Rabbit | Placenta |
Secondary Antibodies | |||||||
Company | Cat # | Antigen Retrieval | Dilution | Incubation | Detection | Control Tissue | |
Immpress HRP Anti-Rabbit IgG | Vector Labs | MP-7401 | - | Ready to use | 1 h, RT | DAB Peroxidase substrate kit (SK-4100) | - |
Immpress HRP Anti-Mouse IgG | Vector Labs | MP-7402 | - | Ready to use | 1 h, RT | DAB Peroxidase substrate kit (SK-4100) | - |
Histochemical Staining | |||||||
Hyaluronan | Merck Millipore | 385911 | CB, 60 °C | 1:100 | 1 h, RT | ABC-AP-Kit (Vector Labs, AK-500) and Liquid Permanent Red (Dako, K0640) | Cartilage |
Picrosirius red | Histolab | HL27150.0500 | - | Ready to use | 10 min, RT | Tendon |
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Sántha, P.; Lenggenhager, D.; Finstadsveen, A.; Dorg, L.; Tøndel, K.; Amrutkar, M.; Gladhaug, I.P.; Verbeke, C. Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers 2021, 13, 895. https://doi.org/10.3390/cancers13040895
Sántha P, Lenggenhager D, Finstadsveen A, Dorg L, Tøndel K, Amrutkar M, Gladhaug IP, Verbeke C. Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers. 2021; 13(4):895. https://doi.org/10.3390/cancers13040895
Chicago/Turabian StyleSántha, Petra, Daniela Lenggenhager, Anette Finstadsveen, Linda Dorg, Kristin Tøndel, Manoj Amrutkar, Ivar P. Gladhaug, and Caroline Verbeke. 2021. "Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence" Cancers 13, no. 4: 895. https://doi.org/10.3390/cancers13040895