Research ArticleClinical Studies

Fibroblast Activation Protein and Tertiary Lymphoid Structure in Colorectal Cancer Recurrence

SHIMON HAYASE, NORIKATSU MIYOSHI, SHIKI FUJINO, MASAYOSHI YASUI, MASAYUKI OHUE, SOICHIRO MINAMI, SHINYA KATO, AYUMI NAGAE, YUKI SEKIDO, TSUYOSHI HATA, ATSUSHI HAMABE, TAKAYUKI OGINO, HIDEKAZU TAKAHASHI, MAMORU UEMURA, HIROFUMI YAMAMOTO, YUICHIRO DOKI and HIDETOSHI EGUCHI
Anticancer Research December 2022, 42 (12) 5897-5907; DOI: https://doi.org/10.21873/anticanres.16099

Abstract

Background/Aim: Fibroblast activation protein (FAP) is known to have prognostic significance in colorectal cancer (CRC). However, FAP and tertiary lymphoid structures (TLSs) have not been associated with each other in predicting the prognosis of CRC recurrence. Patients and Methods: FAP expression was evaluated by real-time reverse transcription polymerase chain reaction in 195 CRC patients at Osaka International Cancer Institute (first data set). Immunohistochemistry (IHC) was then performed to stain FAP at the invasive margin (IM) and in the central tumour (CT) in 159 CRC patients at Osaka University Hospital (second data set). Consecutive slides were used to evaluate the presence of TLSs in 159 CRC patients from Osaka University Hospital. Results: The high FAP mRNA expression group (n=82) was associated with poor recurrence-free survival (RFS) compared with the low FAP expression group (n=83) (p=0.004). In the second data set, patients with high FAP expression in CT and TLS absence (n=49) showed significantly poorer RFS compared with those with low expression of FAP in CT and presence of TLSs (n=101) (p=0.002). Conclusion: FAP in the CT combined with TLSs was shown to have significant prognostic value in predicting CRC recurrence after curative resection.

Key Words:

Recurrence of colorectal cancer (CRC) after curative resection in Japan is present in approximately 18.7% of cases, of which 96.5% occurs within 5 years (1). Given that CRC is the third most common cancer worldwide, predicting the possibility of recurrence and taking necessary precautions could greatly increase the quality of life of patients (2). Over the years, the importance of the tumour microenvironment (TME) in tumour recurrence has been increasingly recognized (3). Among TME stromal cells, cancer-associated fibroblasts (CAFs) and immune cells have recently attracted attention.

Fibroblast activation protein (FAP) is a type-II transmembrane serine protease that is typically not expressed in normal fibroblasts (4, 5). Because of the specificity of its expression in the cancer stroma, FAP is recognized as a marker for CAFs (5).

Earlier studies demonstrated that FAP is associated with angiogenesis, immune regulation, drug resistance, and metastasis (6-8). For example, depletion of FAP+ cells has been shown to lead to better preservation of CD8+ tumour-infiltrating lymphocyte functions (9).

Recently, tertiary lymphoid structures (TLSs), lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation, have been associated with the prognosis of CRC (10-12).

Previous studies of the prognostic value of FAP expression in different tumour types, including CRC, have produced conflicting results (13-16). Because of the complexity and crosstalk between tumour stromal cells (17), evaluating one factor alone might not account for the whole picture. Notably, none of these recent studies have addressed the possibility of FAP-positive fibroblasts being associated with lymphoid neogenesis in CRC.

We investigated whether FAP expression at the invasive margin (IM) and in the central tumour (CT) together with TLSs are associated with CRC recurrence after curative resection.

Patients and Methods

FAP expression in a public database. We examined the relationship of FAP expression with CRC prognosis according to The Cancer Genome Atlas (TCGA) database via Xena platform (18).

Clinical tissue samples. Two sets of patients from different hospitals were examined. In the first set, 201 patients with CRC who underwent tumour resection at Osaka International Cancer Institute from 2005 to 2015 were enrolled (Figure 1A). The second set consisted of 252 patients with CRC who underwent tumour resection at Osaka University Hospital from 2011 to 2012 (Figure 1B). Primary CRC specimens were collected after obtaining informed consent from each patient. For histological assessment, the surgical specimens were fixed and embedded. For RNA expression analysis, all sectioned specimens were frozen in liquid nitrogen and stored at −80°C. All patients were followed up according to Japanese guidelines. Clinicopathological factors were classified according to the eighth edition of the Union for International Cancer Control Tumor-Node-Metastasis (TNM) classification. This study was approved by the ethics committee of our institutions (no. 1608057113 at Osaka International Cancer Institute and no.15146 at Osaka University Hospital).

Figure 1.
Figure 1.

Flow charts of the study population and Kaplan–Meier curves based on fibroblast activation protein (FAP) expression. (A) Flow chart of the study population for data set 1. (B) Flow chart of the study population for data set 2. (C) Kaplan–Meier curves for high and low expression of FAP from The Cancer Genome Atlas (TCGA) database via Xena platform (p=0.03). (D) Kaplan–Meier curves based on FAP expression in 165 colorectal cancer (CRC) patients with curative resection from data set 1 (p=0.004). Cut-off was set at the median 3.52. RFS: Recurrence-free survival. p-Value <0.05 was considered statistically significant.

RNA preparation and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One hundred ninety-five samples from the first set of patients were used to quantify FAP gene expression. Total RNA was prepared using an RNA Purification Kit (Qiagen GmbH, Hilden, Germany) and reverse transcription was performed with a Transcriptor First Standard cDNA Synthesis Kit (Roche Diagnostics, Tokyo, Japan). qRT-PCR was performed using FastStart TaqMan Probe Master (Roche Diagnostics), Universal ProbeLibrary platform (Roche Diagnostics), and CFX Connect Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA, USA) for cDNA amplification of target genes. The primers and Universal ProbeLibrary probes of FAP were as follows: forward, 5′-TGGCGATGAACAATA TCCTAGA-3′; reverse, 5′-ATCCGAACAACGGGATTCTT-3′, UPL #19. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene (forward, 5′-AGCCACATCGCTCAGACAC3′; reverse, 5′-GCCCAATACGACCAAATCC-3′, UPL #60) was used as a housekeeping gene. Relative mRNA expression levels of FAP were normalized to those of GAPDH.

Immunohistochemistry. For FAP staining, 159 CRC surgical specimens from the second set were formalin-fixed and paraffin-embedded and then cut into 3.5-μm-thick sections. After deparaffinization and blocking, the sections were incubated with anti-fibroblast activation protein rabbit monoclonal antibody (1:100, cat. no. Ab207178; Abcam, Cambridge, UK) overnight at 4°C.

For TLS staining, 157 CRC surgical specimens from the second set underwent haematoxylin and eosin (HE) staining. Ten random consecutive samples of CRC surgical specimens from the second patient set were chosen to stain for TLSs. After deparaffinization and blocking, the sections were incubated with anti-CD3 rabbit monoclonal antibody (1:50, cat. no. Ab16669; Abcam) and anti-CD20 mouse monoclonal antibody (1:500, cat. no. 60271-1-Ig; Proteintech, Rosemont, IL, USA) overnight at 4°C. VECTSTAIN Elite ABC-Peroxidase Kit (Vector Laboratories, Burlingame, CA, USA) was used to detect the signal. Diaminobenzidine was used for colour modification, and all sections were counterstained with haematoxylin.

FAP scoring. For FAP evaluation, slides were reviewed by three independent reviewers using a microscope (BZ-X800, KEYENCE Corp., Osaka, Japan). Invasive margins (IMs) were defined as regions 500-μm inside and outside of the invasive front of the tumour. CT was defined as anything inside the IM. Hotspots were chosen by viewing the entire section and within a 500-μm-sized square: >70% stromal staining was considered high; 25%-70% stromal staining was intermediate; and <25% stromal staining was scored as low. Each slide was scored at the IM and CT separately.

TLS scoring. For TLS evaluation, slides were reviewed by three independent reviewers using a microscope (BZ-X800). First, the HE-stained slides were reviewed at 10× power and categorized as TLSs present or absent. Subsequently, 10 randomly picked consecutive slides were stained for CD3 and CD20 to confirm the validity of TLSs observed on the HE slides.

Statistical analysis. Continuous variables were expressed as means±standard deviations (SDs) or standard errors of the means (SEMs). The relationships between FAP expression and clinicopathological factors were analysed using chi-squared tests. Differences between two independent groups were analysed by Student’s t-tests. Kaplan–Meier survival curves were used to illustrate recurrence-free survival (RFS) and overall survival, and then compared using the generalized log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. All statistical analyses were performed using JMP Pro 16 software (SAS Institute Inc., Cary, NC, USA). p-Values <0.05 were considered statistically significant.

Results

FAP expression in a public database. Based on the TCGA database, we examined the relationship of FAP expression with CRC prognosis via Xena platform. TCGA analysis showed that FAP expression is significantly related to CRC overall survival (Figure 1C) (p=0.03).

Patient results. Two sets of data from different hospitals were used to evaluate FAP expression by qRT-PCR and immunohistochemistry (IHC). Data set 1 consisted of 201 patients, from which 6 patients were excluded because of a lack of samples. qRT-PCR was finally performed on 195 specimens.

FAP expression by qRT-PCR. Using qRT-PCR on data set 1, FAP expression normalized by GAPDH levels was divided into two groups at the median (3.52). Patients with values greater than the median were assigned to the high expression group (n=82), and the remainder were categorized as the low expression group (n=83). Table I shows FAP expression in relation to clinicopathological variables (n=165). FAP expression was not significantly related to any of the clinicopathological characteristics. RFS was significantly worse in the high expression group than in the low expression group (p=0.004; Figure 1D). Univariate and multivariate analyses for RFS showed that lymph node metastasis (p=0.001) and high FAP expression (p=0.041) were independent risk factors for recurrence (Table II).

View this table:
Table I.

Correlation between fibroblast activation protein (FAP) expression and clinicopathological factors in 165 colorectal cancer patients with curative resection.

View this table:
Table II.

The univariate and multivariate analyses for recurrence-free survival in 165 colorectal cancer patients with curative resection in regard to fibroblast activation protein (FAP) expression.

FAP expression by IHC. Next, FAP expression in CRC was evaluated in data set 2 (n=148) by IHC. FAP immunohistochemical staining was mainly observed in the stromal area. At the IMs, specimens with greater or equal than 25% of staining in 500-μm squares was considered high (n=100), whereas staining lower than 25% was considered low (n=59) (Figure 2A). The same scoring was undertaken for the CT, resulting in high (n=96) and low (n=63) groups (Figure 2B). Table III and Table IV show the relationship of FAP expression at the CT and IM with clinicopathological variables, respectively (n=159). FAP expression in the CT was significantly related to depth of tumour invasion (p=0.006), lymph node metastasis (p=0.015), lymphatic invasion (p<0.001), and TNM stage (p=0.049). Meanwhile, FAP expression in the IM was significantly related to lymphatic invasion (p<0.001). High FAP expression at the IM and CT tended to be associated with worse RFS (p=0.130 and p=0.077 respectively) (Figure 2C and D).

Figure 2.
Figure 2.

Immunohistochemistry of fibroblast activation protein (FAP) and the recurrence-free survival (RFS) curves. (A) Immunohistochemistry (IHC) staining of FAP in the invasive margin (IM). (B) At the central tumor (CT). (C) Kaplan–Meier curves of RFS based on FAP expression in the IM of 148 colorectal cancer (CRC) patients with curative resection from data set 2 (p=0.130). (D) RFS curves based on FAP expression in the central tumour (CT) of 148 CRC patients with curative resection from dataset 2 (p=0.077). p-Value <0.05 was considered statistically significant.

View this table:
Table III.

Correlation between fibroblast activation protein (FAP) expression in immunohistochemistry at the invasive margin (IM) and clinicopathological factors in 159 patients with colorectal cancer.

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Table IV.

Correlation between fibroblast activation protein (FAP) expression in immunohistochemistry at the central tumor (CT) and clinicopathological factors in 159 patients with colorectal cancer.

TLSs in paraffin-embedded CRC sections. Next, the presence or absence of TLSs on HE slides was evaluated. An example of TLSs is shown in Figure 3A-C. Although a clear definition of TLSs has not been established, the consensus is that CD20+ B cells are adjacent to CD3+ T cell zones, which can also be observed in HE slides. In data set 2, 157 specimens were evaluated and divided into TLSs present (n=76) and TLSs absent (n=81) groups. Table V shows the relationship of TLSs with clinicopathological features (n=157). TLSs were significantly related to preoperative serum CEA levels (p=0.031) and tumour location (left or right, p=0.028; colon or rectum, p=0.038). Absence of TLSs indicated a trend of bad prognosis regarding RFS in 148 CRC patients with curative resection (p=0.057) (Figure 3D).

Figure 3.
Figure 3.

Tertiary lymphoid structures of colorectal cancer patients. (A) Hematoxylin and Eosin staining, (B) immunohistochemistry (IHC) staining of CD3, (C) IHC staining of CD20. (D) Kaplan–Meier curves based on tertiary lymphoid structure (TLS) in 148 colorectal cancer patients with curative resection from data set 2 (p=0.057). FAP: Fibroblast activation protein; IM: invasive margin; CT: central tumour. p-Value <0.05 was considered statistically significant.

View this table:
Table V.

Correlation between tertiary lymphoid structure (TLS) and clinicopathological factors in 157 patients with colorectal cancer.

FAP expression with TLSs. In the same data set 2 (n=148), the combination of FAP expression and TLSs was evaluated. High FAP expression at the IM with TLSs absent (n=51) and low FAP expression at the IM and TLSs present (n=97) (Figure 4A) were grouped separately. As a result, high FAP expression at the IM with TLSs absent was significantly associated with poor prognosis in RFS (Figure 4B) (p=0.029). Meanwhile, high FAP expression in the CT with TLSs absent (n=47) (Figure 4C) was significantly associated with worse RFS compared with low FAP expression at the CT and TLSs present (Figure 4D) (p=0.002). Univariate and multivariate analyses of RFS showed that high FAP expression in the CT with TLSs absent (p=0.033) were independent risk factors for recurrence as well as vascular invasion (p=0.037); however, high FAP expression at the IM with TLSs absent was not a significant independent risk factor (Table VI).

Figure 4.
Figure 4.

Relapse-free survival curves based on fibroblast activation protein (FAP) expression and tertiary lymphoid structures (TLSs). (A) 2×2 diagram of the categorization of high FAP expression in the invasive margin (IM0) with TLS absent (n=51) vs. low FAP expression in invasive margin (IM) and TLS present (n=97). (B) Kaplan–Meier curves based on high FAP expression in IM with TLS absent against low FAP expression in IM and TLS present in 148 colorectal cancer (CRC) patients with curative resection from data set 2 (p=0.029). (C) 2×2 diagram of the categorization of high FAP expression in central tumor (CT) with TLS absent (n=47) vs. low FAP expression in CT and TLS present (n=101). (D) Kaplan–Meier curves based on high FAP expression in CT with TLS absent against low FAP expression in CT and TLS present in 148 CRC patients with curative resection from data set 2 (p=0.002). p-Value <0.05 was considered statistically significant.

View this table:
Table VI.

The univariate and multivariate analyses for recurrence-free survival in 148 colorectal cancer patients with curative resection in regards to fibroblast activation protein (FAP) expression at central tumour (CT) with tertiary lymphoid structure (TLS).

Discussion

Tumour characteristics and TNM staging have long been the gold standards in categorizing cancer stage. However, not only the characteristics of the tumour, but the surroundings of the tumour, are starting to be elucidated regarding their role in “malignant behaviour”, such as recurrence. The interest in the role of the TME has been peaking amongst researchers in the field of cancer. The TME consists of tumour cells, tumour stromal cells, and non-cellular components of extracellular matrix (17).

FAP is a marker for CAFs. In this study, we observed FAP+ CAFs whose expression was specific to the tumour stroma. TLSs, known for aggregating at sites with chronic inflammation, can be observed in the tumour stroma. We used HE staining to determine the presence of TLSs and stained for CD3 and CD20 to confirm the commonly accepted definition of TLSs (19, 20).

Here, we showed that the role of FAP+ CAFs and TLSs could be observed by IHC. The combinations of these factors significantly predicted the RFS rate (p=0.029 and p=0.002, respectively).

The expression of FAP was closely related to patient characteristics, such as tumour depth, lymph node metastasis, lymphatic invasion, and TNM stage. Moreover, TLSs were related to preoperative carcinoembryonic antigen levels and tumour location. We speculated that FAP indicates the characteristics of the tumour itself, while TLSs represent the characteristics of the host (patient).

In this study, FAP at the CT was more significantly related to RFS. Previous papers reported conflicting results as to whether the IM or CT is more significant in prognosis. However, the definition of the IM and the methodology of scoring positive cells lacks consistency. Therefore, we referred to a study describing Immunoscore (21) to produce consistent and reproducible results.

To our knowledge, this study is the first to report the association between FAP and TLSs in the recurrence of CRC. Further research to elucidate the mechanism by which FAP and TLSs affect recurrence is necessary.

In conclusion, FAP is a novel oncogene in CRC. Moreover, FAP in the CT combined with TLSs could be a powerful tool to predict the recurrence of CRC after curative resection.

Acknowledgements

The Authors thank Aya Ito and Ayaka Tojo for the technical assistance.

Footnotes

  • Authors’ Contributions

    S.H. and N.M. contributed to the study conception and design. The first draft of the manuscript was written by S.H. Data assessment was performed by S.F., S.M., S.K., A.N., Y.S., T.H., A.H., T.O., H.T., M.U., H.Y., Y.D., H.E. All Authors commented on the previous version of the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest related to this study.

  • Received October 13, 2022.
  • Revision received October 24, 2022.
  • Accepted October 25, 2022.

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Fibroblast Activation Protein and Tertiary Lymphoid Structure in Colorectal Cancer Recurrence
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