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Prognostic significance of ımmunhistochemical axl expression in pancreas ductal adenocarcinomas


1 Department of Medical Pathology, University of Health Sciences, Izmir Bozyaka Training and Research Hospital, Izmir, Turkey
2 Department of Medical Oncology, University of Health Sciences, Izmir Bozyaka Training and Research Hospital, Izmir, Turkey
3 Department of General Surgery, University of Health Sciences, Izmir Bozyaka Training and Research Hospital, Izmir, Turkey

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Date of Submission09-Oct-2021
Date of Decision17-Dec-2021
Date of Acceptance21-Dec-2021
Date of Web Publication13-Jan-2023
 

   Abstract 


Introduction and Aim: Pancreas Ductal Adenocarcinomas (PDACs) are among the leading causes of cancer-related death. Tyrosine kinase receptors (TKRs) are responsible for cell plasticity, chemoresistance, immunosuppression and metastasis potential. Axl is a receptor of the TKR family, and it has come to the fore in cancer treatment in the last decade. This study aimed to investigate the relationship of immunohistochemical Axl expression with histological features and its prognostic importance in PDACs. Material and Methods: Fifty-three patients who were operated on for PDAC between 2006-2017 were evaluated retrospectively. Features of tumors; size, lymphovascular invasion (LVI), perineural invasion (PNI), resection margin (RM), lymph node metastasis (LNM), differentiation, tumor-infiltrating lymphocyte, stage and overall survival were recorded. Immunohistochemically, membranous and or cytoplasmic staining was considered positive for Axl. Statistically, Pearson Chi-Square, Cox regression and Kaplan Mayer tests were used in the SPSS 21.0 program. Results: Axl was positive in 28 patients (52.8%). Axl positivity was found to be associated with the presence of LVI (P = 0.009) and LNM (P = 0.002) and was an independent prognostic factor in short survival (P = 0.006). Conclusion: It was found that increased expression of Axl, which is known to increase EMT-mediated metastasis in carcinogenesis, may be an indicator of local spread and poor prognosis in PDAC patients. In this respect, it can be promising as a targeted molecule in PDAC patient's individualized treatments.

Keywords: Axl, pancreas ductal adenocarcinomas, prognosis, targeted therapy, TKRs


How to cite this URL:
Oz O, Argon A, Kebat TA, Ozdemir O, Yakan S. Prognostic significance of ımmunhistochemical axl expression in pancreas ductal adenocarcinomas. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Feb 2]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=367698





   Introduction Top


Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most aggressive malignant tumors.[1],[2],[3],[4],[5] They are known to relapse early, have a high rate of distant metastases and have resistance to most chemotherapy regimens.[2],[6],[7] Although some are still controversial, histopathological subtype, tumor size, differentiation, perineural and lymphovascular invasion, regional lymph node metastasis and surgical margin positivity are the main prognostic parameters.[5],[8] For targeted personalized therapies, the molecular mechanisms of PDAC have not been adequately deciphered, either in terms of cancer cells or the tumor microenvironment.[1],[2],[9],[10],[11],[12]

In an animal model, it has been shown that mesenchymal-like tumor cells in PDAC are crucial in the stage of chemotherapy resistance and metastasis of malignancies.[13] These cells usually contain the high-level expression of the protein Axl, a receptor tyrosine kinase (RTK), and in this way can evade some immunomodulatory steps.[14] Axl-RTK is a TAM receptor family member (TYRO3, Axl, MERTK).[15],[16],[17] Recently, it has been reported that the interaction of peritumoral cancer cells and cancer-associated fibroblasts is regulated through the GAS6/AXL axis in pancreatic ductal adenocarcinoma (PDAC) cancer cells, and high gene expression of Axl is associated with poor prognosis in PDAC.[18] After binding its specific ligand GAS6 (growth-arrest-specific protein 6) protein, Axl triggers for many cell functions. It has been shown that these pathways are associated with cell proliferation, migration, survival, and EMT (PI3K, MAPK, STAT, and NF-κβ) [Figure 1].[13],[17],[19],[20],[21],[22],[23],[24],[25] However, its critical role in cancer cells is not yet clearly known. Axl deserves to be a target for personalized cancer treatments because of its impact on many pathways involved in carcinogenesis. Some Axl inhibitors have been continuing to research, and some clinical trials in breast cancer have high Axl expression levels in the United States have been continuing.[17]
Figure 1: The pathways controlled by the Axl receptor; Dimerization and activation of Axl receptor by binding of Gas 6 molecule provides proliferation via Ras/Raf/ERK1 / 2 pathway, survival, and migration via PI3K pathway. Axl induces epithelial-mesenchymal transformation (EMT) by attaching a phosphate group to different regions of Smad3 via JNK[24,25] Abbreviations: JNK: c-Jun N-terminal kinase, SMAD: mothers against decapentaplegic homolog

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It is claimed that high Axl gene expression in cancer cells can be associated with a poor prognosis in the literature. Some of them are brain, breast, lung, and pancreatic cancers.[19],[20],[26],[27],[28],[29],[30],[31],[32] There are very few publications on the role of this molecule in PDACs, which has a very high potential for widespread metastatic spread, and there are still not enough clinical studies.[30],[31],[32]

This study aimed to investigate the immunohistochemical Axl expression in PDAC cancer cells, its relationship with histopathological features and its prognostic importance.


   Material and Methods Top


Clinicopathological data

Fifty-three patients who underwent pancreaticoduodenectomy (Whipple operation) for pancreatic mass between 2006 and 2017 in one institution and were diagnosed with PDAC pathologically were included in this study. Patients who received neoadjuvant chemotherapy did not have a tumor suitable for evaluation and whose survival data could not be acquired were excluded from the study. At least two pathologists re-evaluated Hematoxylin-Eosin-stained sections of all cases, and pathological findings were recorded in a standard format. Tumor size was recorded numerically. Differentiation was classified as well - moderate - poor, perineural invasion (PNI) and lymphovascular invasion (LVI) were classified as present or absent, tumor-infiltrating lymphocyte (TIL) was classified as none, weak, moderate, dense. The presence of macroscopic or microscopic tumor at the resection margin (RM) was accepted as resection margin positivity (RM0 = negative surgical margin, RM1 = positive surgical margin). The stage was classified using the World Health Organization's Tumor Classification of Gastrointestinal Tract Tumors. The demographical features of the cases and the macroscopic features of the tumors were obtained from the hospital archive system. Tumor tissue and tumor microenvironment were evaluated for TIL scoring and only PDAC cells were evaluated for determination of immunohistochemical (IHC) Axl staining. The TIL scoring system was scored according to the scoring system reported by Zhang et al.[33] The lymphocytic response was divided into four categories; 0 (none): no infiltrating lymphocytes, 1 (weak): slight increase in infiltrating lymphocytes in tumor tissue or stroma, 2 (moderate): moderate increase in infiltrating lymphocytes intertwined with tumor tissue, 3 (dense): strong density of infiltrating lymphocytes in tumor tissue and presence of lymphoid clusters.

Immunohistochemistry

4-micron-thick sections were obtained for IHC investigation by choosing one of the blocks that had gone through the routine process and best reflected the tumor features. Axl (C89E7) Rabbit monoclonal Ab (#8661 Cell Signaling, 1:50 delusion, catalog number: 8661S) primary antibodies were used for immunohistochemically Axl expression. The Axl antibody was incubated at 37°C for 32 minutes. Antibody binding was revealed by Ultra View Universal DAB detection kit in a Benchmark XT auto Stainer (Ventana, Tucson, AZ, USA). A cell paraffin block of SNU-449 cell line known to have a high level of Axl protein expression was used as the positive control. Cytoplasmic and/or membranous immunohistochemical staining was considered positive for Axl protein expression. At least ten high power fields (HPF) were evaluated for each tumor. Immunohistochemical staining was evaluated into two categories. The negative staining: positive tumor cell percentage was ≤ 1% and the positive staining: positive tumor cell percentage was > 1% [Figure 2]. In tumors showing heterogeneity of staining, the immunostaining was judged according to the most intense staining pattern. All assessments were made by pathologists blinded to the prognostic information.
Figure 2: Examples of İmmunohistochemical staining of AXL Expression in Pancreas Ductal Adenocarcinoma cases; AXL protein expression was detected by IHC staining in 28 (52.8%) of 53 PDAC. Positive Axl staining of PDAC cells was accepted whenever localized either in the cytoplasm or on the cell membrane. Intensive positive Axl staining in PDAC (x10) (left upper figure) The examples of positive Axl staining of varying intensity in the tumoral glands or tumor cells of PADC (x20)

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Survival data

Prognostic information regarding patient follow-up was obtained from the Local Cancer Monitoring archive records and Follow-up Center. The time between the date of resection and the date of death was calculated as the overall survival (OS). The time between the date of resection and last observation was calculated as the overall survival (OS) for living patients. The patients' follow-up data was updated in August 2021.

Statistical analysis

Statistically, the Chi-square test, Cox-regression test, and Kaplan-Meier test were performed with the IBM SPSS® software V21.0. The P value ≤ 0.05 was accepted statistically significant in all statistical analyses.

Ethics and disclosure of potential conflicts of interest

All procedures performed in this study following the Declaration of Helsinki on the medical protocol following the 1964 Helsinki declaration, its later amendments, and ethics, and the National Research Ethical Review Board approved the study (Reference Number: 15345988-16 Date: July sixth, 2020). All authors have accepted that no conflict of interest could influence this paper's content. They participate in the research and article preparation.


   Results Top


Patients' characteristics

Our patient group includes30 men (56.6%) and 23 women (43.4%). The median age of patients was 65.00 years (range: 37-80, mean: 64.37 ± 9.12). The mean survival time was 24,755 ± 4,682 months. The cumulative proportion surviving at 12th month, 24th months, 48th months were 73.6%, 52.8% and 9.4%, respectively.

The mean tumor size was 3.23 ± 2.19 cm, and the median tumor size was 3.00 cm (range, 1.20–6.50 cm). Tumor size (P = 0.560), age (P = 0.099) and gender (P = 0.922) were not associated with the OS time.

The histopathological features

Statistically, poor differentiation was related with presence of LVI (P = 0.021), PNI (P = 0.005), advanced stage (P < 0.000) and pT (P = 0.003), presence of lymph node metastasis (P = 0.017). PNI (P < 0.000) and lymph node metastases (P < 0.000) were more common in the presence of LVI, and more surgical margin positivity was observed in cases with LVI (P = 0.006). PNI was associated with advanced pT (P = 0.032), pN (P < 0.000) and stage (P = 0.007), and cases with positive surgical margins had more advanced pT (P = 0.035).

The number of cases according to histopathological features and their relationship with overall survival time was shown in [Table 1].
Table 1: The number of cases according to histopathological features and their relationship with overall survival time

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Immunohistochemical Axl expression

Immunohistochemically, Axl was negative in 25 tumors (47.2%). We determined a strong relationship between the Axl positivity and short OS time (P = 0.006). Moreover, Axl positivity was correlated with the presence of LVI (P = 0.009) and lymph node metastasis (P = 0.002). The parameters affecting prognosis and their Kaplan Maier plots are shown in [Figure 3]. In the statistically multivariable model for PNI, LVI, and Axl staining, Axl staining was an independent adverse prognostic factor (P = 0.018; hazard ratio: 2,101 (95% confidence interval: 0.137-3.883)). The relationship between Axl staining with demographical and pathological features is shown in [Table 2].
Figure 3: The parameters affecting prognosis and their Kaplan Maier plots: a: Axl expression is associated with adverse prognosis in pancreatic ductal adenocarcinoma (P = 0.006). Kaplan Meier survival analysis confirms that patients with Axl-expressing tumors demonstrate a significantly shorter median survival than those with Axl-negative cancers. b: Lymphovascular invasion is associated with adverse prognosis in pancreatic ductal adenocarcinoma (P = 0.021). c: Perineural invasion is associated with adverse prognosis in pancreatic ductal adenocarcinoma (P = 0.043)

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Table 2: The relationship Axl staining with demographical and pathological features

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   Discussion Top


PDAC is one of the most aggressive malign solid tumors with a high mortality rate and does not have an effective treatment protocol.[3],[4],[10],[34],[35] It is the fourth rank responsible for cancer-related deaths worldwide, and it is estimated to rank second by 2030, especially in developed countries.[34],[36],[37] Despite the highly aggressive treatment process, the 1-year survival rate is 20%, and the 5-year survival rate is around 5% and this could not be changed for a long time, unlike the other cancers.[1],[4],[34],[35] The results of our group survival rate were also similar to the literature. The average survival time of our patients who did not receive neoadjuvant treatment and had operable tumors was approximately two years. While the cumulative proportion surviving at 12th month was 73.6%, this rate decreased below 10% after the 4th year. These realities suggest that PDAC patients urgently need better management, primarily targeted molecular therapies. The inadequacy of the existing treatment methods is apparent, and the literature expectation on targeted molecular treatment methods is also in this direction.[1],[2],[9],[10],[11],[12]

In our study group, PNI, LVI and Axl positivity was found to be poor prognostic features. Although the relationship between the presence of PNI and LVI and short survival has been known for a long time,[8] this feature of Axl positivity has been shown in very few studies. Our study, which includes similar results, is among the pioneering studies targeting Axl and sheds light on the literature.[30],[31] In addition, the 52.8% Axl positivity rate we found in our study was the closest to the 55% rate in the study of Koorsta et al.,[32] which is the first study on this subject.

PDAC patients are usually in the advanced stage when recognized. The PDAC cases usually give late clinical symptoms depending on localization and do not have an effective screening program.[2],[7],[34],[35] Unfortunately, only 20% of tumors are eligible for resection at the diagnosis time, and patients have a no different survival time of patients who have the local advance/unresectable tumors taking neoadjuvant therapy.[1],[6],[35] Many innovative treatment models, including immunotherapy, therapeutic vaccines, and adoptive T-cell transfer, have been experimented with in PDAC patients, but no significant results have been achieved.[4],[10],[11] Although there are candidate molecules targeting tumor cells such as EGFR, EGFR receptor antagonists, unfortunately, could not provide the expected recovery in these tumors.[1],[3],[4],[12],[30] The RTKs play many essential roles in signal conversion in normal and malignant cells, and they are attractive molecules in targeted individuals' therapy.[13],[17],[38],[39] There are many RTKs with differentiated extracellular domain-ligand binding sites. Axl RTK is a TAM receptor family member (TYRO3, Axl, MERTK). RTKs and so Axl is thought to be responsible for cell plasticity, chemoresistance, angiogenesis, immunosuppression, and metastasis potential.[15],[16],[19],[31],[40] Pancreatic cancers are known for their three predominant features: high metastasis rate, resistance to chemotherapy, and immunosuppression.[13] Although there are many mechanisms for the tumor to acquire these characteristics, it is now known that mesenchymal-like cancer cells also play a significant role in chemotherapy resistance and metastasis in PDAC.[13] Also, mesenchymal-like tumor cells have been shown to have high Axl expression.[13],[14],[21] Although this study was performed only on operable tumors, immunohistochemical Axl expression could be detected in approximately half of the tumors. Moreover, focal, and low ratio staining was observed in some of the tumors. Although we could not determine the nature of the cells showing positivity with the methods we used, it can be thought that these cells are mesenchymal-like PDAC cells in the light of the literature. Considering that the overall survival time in patients with tumors showing immunohistochemical Axl expression is shorter than in other cases and that statistically staining is an independent prognostic factor, it has been suggested that Axl-expressing tumor cells may be the cells responsible for the aggressiveness of the tumor. Therefore, Axl appears to be an exciting candidate for the individualized treatment of PDACs.

In addition, a positive correlation was found between Axl staining and the presence of LVI and lymph node metastasis in comparative statistical analyzes in our series [Table 2]. Similarly, Koorstra et al.[32] reported that Axl positivity was associated with LNM. Moreover, their studies have shown that when AXL signaling in a PDAC cell line is blocked, the migration and invasion of cancer cells are reduced. As it is known, LVI is one of the first steps on the path to LNM and is considered an indicator of the local aggressiveness of the tumor. Therefore, it is not surprising that Axl expression, which is thought to play a role in tumor invasion and metastasis, is associated with these morphological findings. The results of our study support this expected finding in terms of tumor pathogenesis.

It has been demonstrated that anti-human AXL monoclonal antibodies can abolish specific effects in the downstream pathway of this molecule both in pancreatic cancer cell lines and in vivo[30] and some other tumor cell lines.[40] Clinical data with Axl inhibition in pancreatic cancer are not yet available. However, some clinical studies are in the planning stages to test the effect of inhibiting Axl in combination with standard therapy in pancreatic cancer patients.[13] As a result of these studies, we can say that it may be possible to confirm the role of Axl as a therapeutic target in pancreatic cancer. In conclusion, we demonstrated that even a tiny level of expression of Axl RTK in tumor cells in PDAC contributes a negative prognostic effect on the overall survival of patients in this work. This result may support that Axl, a membrane-localized receptor, is a promising therapeutic target for targeted therapy in Axl positive PDAC patients who have not benefited from long-standing existing treatment options. We hope that comprehensive clinical trials to be performed in PDAC with Axl RTK inhibition will enable us to obtain positive objective patient-based treatment response data in a short time.

Key messages

  • This article is one of the pioneering studies on the immunohistochemical expression of the Tyrosine Kinase Family receptor Axl in pancreatic cancers.
  • Evaluation of all prognostic histopathological data in a homogeneous patient group and showing that Axl expression is an independent prognostic factor among all data with the applied multi-step statistical method shows that this study has the power to contribute to the literature.
  • Ultimately, we argue that Axl expression is one of the issues that needs to be addressed and explored in the development of new targeted therapies.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Ozden Oz,
Department of Pathology, Izmir Bozyaka Training and Research Hospital, University of Health Sciences, Izmir
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1002_21



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