Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Tissue Samples
2.2. Immunohistochemistry
2.3. Digital Pathology Image Analysis
2.4. Marker Staining
2.5. FGS Criteria
- a median H-score in (pre)malignant tissue being at least twice as high as the median H-score in healthy control and stromal tissue [34];
- a minimum median H-score in (pre)malignant tissue of at least 25;
- homogeneous expression throughout the tumor;
- cell surface protein expression.
2.6. Statistics
3. Results
3.1. Tissue Characteristics
3.2. Immunohistochemical Marker Staining
3.2.1. αvβ6—Integrin Alphavbeta6
- Stromal tissue lacked αvβ6 expression. Healthy vulvar epithelium showed no or low expression of αvβ6. If αvβ6 was present in healthy vulvar tissue, it was mainly located in the spinosal and basal layer of the epithelium (Figure 1A). In addition, αvβ6 expression was higher in normal vulvar tissues wherein sebaceous glands were present (11/15 healthy vulvar tissues) compared with vulvar tissue sections that lacked those glands. αvβ6 staining within sebaceous glands was low to moderate (Figure 1A). The median H-score of healthy vulvar tissue was significantly lower compared with median H-scores of all vulvar (pre)malignant tissue types (Figure 2), resulting in TBRs > 2 (Table 2).
- Moderate αvβ6 expression was observed in 4/8 dVIN, 14/16 HPV-independent VSCC, 4/13 HSIL and 10/13 HPV-dependent VSCC tissues (Figure 1B–E respectively). αvβ6 expression lacked in 2/16 HPV-independent VSCC and 3/13 HPV-dependent VSCC tissues. The other premalignant tissues showed low expression. More intense αvβ6 staining was found in HSIL adjacent to HPV-dependent VSCC (average H-score 42) compared with isolated HSIL (average H-score 114). This difference was not observed for dVIN. Median H-scores per vulvar (pre)malignant tissues type were all above 25 (Table 2).
- αvβ6 was homogeneously expressed in all HPV-independent VSCC tissues. 2/10 HPV-dependent VSCC tissues showed a patchy staining pattern throughout the tumor, for 2/10 expression was restricted to the spinosal and/or basal layers, the remainder showed homogeneous expression. To a greater or lesser extent in all dVIN and HSIL tissues, as for healthy vulvar tissue, αvβ6 expression was restricted to the spinosal and/or basal layers (Figure 1A,D).
- αvβ6 showed cell membrane staining.
3.2.2. CAIX—Carbonic Anhydrase IX
- Stromal and healthy vulvar epithelium lacked CAIX staining (Figure 1F). The median H-score of healthy vulvar tissues was significantly lower compared with median H-scores of dVIN, HSIL and HPV-dependent VSCC tissue groups (Figure 2), resulting in TBRs > 2 (Table 2). The median H-score of HPV-independent VSCC tissue group was not tested significantly higher compared with the median H-score of healthy vulvar tissue (TBR 4.5, Table 2).
- If CAIX staining was observed, it was positioned in the spinosal and/or basal layers of the vulvar epidermis in a heterogeneous and patchy pattern (Figure 1G–J).
- CAIX showed cell membrane staining.
3.2.3. CD44v6—CD44 Variant 6
- Stromal tissue lacked CD44v6 staining. Healthy vulvar epithelium showed in 7/15 tissues high CD44v6 expression, the remaining tissues showed moderate expression (Figure 1K). TBRs were inverse for all (pre)malignant vulvar tissue types, indicating downregulation of CD44v6 in (pre)malignant compared with healthy tissue (Figure 2). Consequently, TBRs were not in favor for FGS application at the surface of the vulva (Table 2).
- Predominantly moderate CD44v6 staining was observed in vulvar (pre)malignant tissues (Figure 1L–O), in 5/10 dVIN, 3/16 HPV-independent VSCC, 5/15 HSIL and 1/12 HPV-dependent VSCC tissues high CD44v6 expression was observed. Median CD44v6 H-scores per vulvar (pre)malignant tissues type were all above 25 (Table 2).
- CD44v6 showed homogenous expression.
- CD44v6 showed cell membrane staining.
3.2.4. EGFR—Epithelial Cell Adhesion Molecule
- EGFR staining was observed in glands, blood vessels and adnexa. Healthy vulvar epithelium showed moderate EGFR expression in 10/15 tissues (Figure 1P) and low expression in 5/15 tissues. TBRs were inverse for all (pre)malignant vulvar tissue types, indicating downregulation of EGFR in (pre)malignant tissue compared with healthy (Figure 2) Consequently, TBRs were not in favor for FGS application at the surface of the vulva (Table 2).
- EGFR was moderately expressed in 5/10 dVIN, 11/16 HPV-independent VSCC, 5/15 HSIL and 2/13 HPV-dependent VSCC tissues (Figure 1Q,R), the expression in the remaining samples was low (Figure 1S,T, except 1 HPV-independent VSCC with high expression). HSIL showed a median H-score below 25, the H-scores for other vulvar (pre)malignant tissue types were at least 25 (Table 2).
- EGFR was gradually expressed in healthy vulvar epithelium, being more strongly expressed in the stratum basal compared with the stratum corneum. For (pre)malignant tissues the expression patterns were diverse. Homogenous (Figure 1R), patchy (Figure 1Q,S) and on/off expression patterns (Figure 1T) were observed in these tissues.
- EGFR showed cell membrane staining.
3.2.5. EpCAM—Epithelial Cell Adhesion Molecule
- EpCAM staining was not observed in stromal tissue, except for the endothelial lining of blood vessels. Healthy vulvar epithelium lacked EpCAM expression (Figure 1U). The median H-score of healthy vulvar tissue was not significantly different compared with any vulvar (pre)malignant tissue group (Figure 2), resulting in TBRs < 2, except for dVIN with an TBR of 2.5 (Table 2).
- No pattern could be recognized due to the low expression of EpCAM in vulvar tissues.
- EpCAM showed cell membrane staining on the endothelial lining of blood vessels.
3.2.6. FRα—Folate Receptor α
- No pattern could be recognized due to the low expression of FRα in all vulvar tissues.
- Cell membrane staining for FRα was observed in lung tumor tissue (control).
3.2.7. MRP1—Multidrug Resistance-Associated Protein
- Low to moderate MRP1 staining was observed in stromal cells and several sebaceous glands of a few healthy and (pre) malignant tissues. No MRP1 expression was observed in healthy vulvar epithelium (Figure 1EE). The median H-score of healthy vulvar tissue was not significantly lower compared with any median H-score of (pre)malignant tissues (Figure 2), resulting in TBRs < 2 (Table 2).
- No expression pattern could be recognized due to the overall low expression of MRP1.
- In both stromal vulvar tissue as in placental tissue (control), cytoplasmatic and membranous presence of MRP1 was observed on cells.
3.2.8. MUC1—Mucin 1
- Stromal tissue lacked MUC1 staining, except for sebaceous glands positioned in the dermis, which showed moderate or high MUC1 expression (Figure 1JJ). Half of the healthy vulvar epithelial tissues lacked MUC1 expression (Figure 1JJ), others showed low expression restricted to the stratum spinosum. The median H-score of healthy vulvar tissue was significantly lower compared with median H-scores of all vulvar (pre)malignant tissue types (Figure 2), resulting in TBRs > 2 (Table 2).
- Moderate MUC1 expression was observed in 5/10 dVIN (Figure 1 KK), 6/16 HPV-dependent VSCC, 6/14 HSIL and 7/13 HPV-dependent VSCC tissues, the remaining tissues showed low expression (Figure 1LL–NN). Median H-scores for MUC1 expression per vulvar (pre)malignant tissues type were all above 25 (Table 2).
- The expression pattern was heterogenous and patchy throughout all tissue samples.
- MUC1 showed cell membrane staining.
3.2.9. uPAR—Urokinase Plasminogen Activator Receptor
- Low stromal expression of uPAR was observed in healthy and (pre)malignant tissues. Healthy vulvar epithelium lacked uPAR staining(Figure 1OO). The median H-score of healthy vulvar tissues was significantly lower compared with median H-scores of dVIN, HPV-dependent and independent VSCC tissue groups (Figure 2), resulting in TBRs > 2 (Table 2). For the HSIL group, the TBR < 2.
- Moderate uPAR expression was observed in 4/12 HPV-independent VSCC (Figure 1QQ), 1/12 HSIL and 2/12 HPV-dependent VSCC tissues (Figure 1SS), the remaining vulvar (pre)malignant tissues showed low or absent expression (Figure 1PP,RR). Only the median H-score for uPAR expression in the HPV-independent VSCC tissue group was above 25 (Table 2).
- uPAR was heterogeneously expressed throughout (pre)malignant vulvar tissue.
- uPAR showed cell membrane staining and sometimes cytoplasmatic staining in cells.
3.3. Evaluation of FGS Criteria
3.4. αvβ6 Expression in Individual VSCC Tissue Sections
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Biomarker | Source | Clone Number | Catalogue Number | Stock | Dilution | Antigen Retrieval | Positive Control |
---|---|---|---|---|---|---|---|
αvβ6 | Biogen, Inc., Cambridge, MA, USA | 6.2A1 | 62A1CEO2 | 50 µg/mL | 1/100 | 0.4% pepsin (S3002 Agilent) 37 °C for 15 min. | Normal colon |
CA IX | Santa Cruz Biotechnology, Inc., Danvers, MA, USA | H-11 | Sc-365900 | 200 µg/mL | 1/2500 | Target retrieval solution, pH 6.1 (K8005 Agilent) | Normal stomach |
CD44v6 | Abcam, Cambridge, UK | VFF7 | ab30436 | 1 mg/mL | 1/3200 | Target retrieval solution, pH 6.1 (K8005 Agilent) | Normal skin |
EGFR | Dako, Glostrup, Denmark | E30 | M7239 | 286 µg/mL | 1/600 | 0.4% pepsin (S3002 Agilent) 37 °C for 10 min. | Normal placenta |
EpCAM | LUMC, department of pathology 1 | 323/A3 | - | 0.4 mg/mL | 1/1600 | 0.1% trypsin (T7409 Sigma Aldrich) 37 °C for 30 min. | Colon tumor |
FRα | BioCare Medical, Pacheco, CA, USA | 26B3.F2 | BRI 4006K AA (kit) | Assay kit | N.A. | Ready-to-use | Lung tumor |
MRP1 | Santa Cruz Biotechnology, Inc., Danvers, MA, USA | QCRL-1 | Sc-18835 | 200 µg /mL | 1/400 | Target retrieval solution, pH 6.1 (K8005 Agilent) | Normal placenta |
MUC1 | Invitrogen, Waltham, MA, USA | E29 | MA5-14077 | 0.2 mg/mL | 1/4800 | Target retrieval solution, pH 9.0 (K8004 Agilent) | Normal colon |
uPAR | Monopar 2 | ATN617 | - | 0.48 mg/mL | 1/200 | Target retrieval solution, pH 6.1 (K8005 Agilent) | Colon tumor |
p16 | Roche, Almere, The Netherlands | E6H4 | 06695248001 | Ready-to-use | 1/25 | TRIS/EDTA | Normal cervix |
p53 | DAKO, Santa Clara, CA, USA | DO-7 | GA61661-2 | Ready to use | 1/2000 | TRIS/EDTA | Normal cervix |
αvβ6 | CAIX | CD44v6 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Median | Min | Max | TBR | Median | Min | Max | TBR | Median | Min | Max | TBR | |
Healthy (n = 15) | 9 | 2 | 31 | - | 2 | 0 | 19 | - | 240 | 173 | 283 | - |
dVIN (n = 10) | 59 b | 20 | 216 | 6.6 | 7 b | 1 | 65 | 3.5 | 248 | 123 | 275 | 1.0 |
HPV− VSCC (n = 16) | 118 | 0 | 231 | 13.1 | 9 a | 1 | 77 | 4.5 | 196 | 96 | 271 | 0.8 |
HSIL (n = 15) | 42 b | 3 | 145 | 4.7 | 5 | 1 | 92 | 2.5 | 223 | 119 | 279 | 0.9 |
HPV + VSCC (n = 13) | 93 | 7 | 213 | 10.3 | 6 | 1 | 102 | 3.0 | 118 a | 51 | 267 | 0.5 |
EGFR | EpCAM | FRα | ||||||||||
Median | Min | Max | TBR | Median | Min | Max | TBR | Median | Min | Max | TBR | |
Healthy (n = 15) | 61 | 2 | 200 | - | 2 | 0 | 12 | - | 3 | 1 | 43 | - |
dVIN (n = 10) | 40 | 2 | 138 | 0.7 | 5 | 0 | 11 | 2.5 | 1 | 1 | 3 | 0.3 |
HPV− VSCC (n = 16) | 129 | 4 | 253 | 2.2 | 3 | 0 | 17 | 1.5 | 4 a | 2 | 7 | 1.3 |
HSIL (n = 15) | 10 | 0 | 213 | 0.2 | 2 | 0 | 17 | 1.0 | 2 | 0 | 28 | 0.7 |
HPV + VSCC (n = 13) | 25 | 5 | 106 | 0.4 | 7 a | 0 | 91 | 3.5 | 4 | 2 | 60 | 0.3 |
MRP1 | MUC1 | uPAR | ||||||||||
Median | Min | Max | TBR | Median | Min | Max | TBR | Median | Min | Max | TBR | |
Healthy (n = 15) | 4 | 0 | 29 | - | 11 | 1 | 81 | - | 6 | 1 | 22 | - |
dVIN (n = 10) | 8 | 0 | 24 | 2.0 | 63 | 20 | 206 | 5.7 | 12 b | 2 | 35 | 2.0 |
HPV− VSCC (n = 16) | 13 c | 0 | 42 | 0.3 | 34 a | 3 | 184 | 3.1 | 37 c | 5 | 91 | 6.2 |
HSIL (n = 15) | 2 | 0 | 22 | 0.5 | 40 | 3 | 201 | 3.6 | 6 c | 0 | 73 | 1.0 |
HPV + VSCC (n = 13) | 2 | 0 | 17 | 0.5 | 62 | 14 | 176 | 5.6 | 19 a | 1 | 125 | 3.1 |
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Huisman, B.W.; Cankat, M.; Bosse, T.; Vahrmeijer, A.L.; Rissmann, R.; Burggraaf, J.; Sier, C.F.M.; van Poelgeest, M.I.E. Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions. Cancers 2021, 13, 6006. https://doi.org/10.3390/cancers13236006
Huisman BW, Cankat M, Bosse T, Vahrmeijer AL, Rissmann R, Burggraaf J, Sier CFM, van Poelgeest MIE. Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions. Cancers. 2021; 13(23):6006. https://doi.org/10.3390/cancers13236006
Chicago/Turabian StyleHuisman, Bertine W., Merve Cankat, Tjalling Bosse, Alexander L. Vahrmeijer, Robert Rissmann, Jacobus Burggraaf, Cornelis F. M. Sier, and Mariette I. E. van Poelgeest. 2021. "Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions" Cancers 13, no. 23: 6006. https://doi.org/10.3390/cancers13236006