Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

doi:10.21203/rs.3.rs-2476989/v1

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Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

https://doi.org/10.21203/rs.3.rs-2476989/v1

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Purpose Detecting tumor progression remains difficult in patients with glioma. Fibroblast activation protein (FAP) in gliomas has been showed to promote tumor progression. Glioma-circulating biomarkers have not yet been used in clinical practice. This study seeks to evaluate the feasibility of glioma detection using a serum FAP marker.

Methods We adopted enzyme-linked immunoadsorbent assay (ELISA) to determine serum FAP level in 87 gliomas. The relationship between preoperative serum FAP levels and postoperative pathology, as well as molecular pathology was investigated. Serial FAP tests were performed in 33 malignant gliomas to see if they could track the disease when compared to image findings. Immunohistochemistry was performed on four gliomas using a FAP-specific antibody to confirm FAP expression in tumors. Therelationship between tumor burden as determined by volumetric analysis and serum FAP level was investigated.

Results Serum FAP was significantly elevated in a large proportion of gliomas, was closely related to histopathology and molecular pathology, and longitudinally fluctuated and varied with the disease stage. The significant increase in serum FAP was associated with tumor progression and/or worsening symptoms.

Conclusions Serum FAP can be used to detect the disease as a biomarker. Its detection in conjunction with MR imaging may allow for more precise and immediate diagnosis.

Glioma

Fibroblast activation protein

Image

Serum

Dynamic detection

Glioma as the most common primary malignant brain tumor in adults, is regarded as one of the leading causes of cancer death worldwide [1, 2]. Despite significant advances in treatment, patients with glioma, particularly high-grade glioma, continue to have a poor prognosis. According to a multicentric data, the median overall survival of glioblastoma (GBM) patients is approximately 15 months, with a 5-year survival rate of < 10% [1, 3].

The resected tumor or biopsy tissue allows direct access to genetic information or immunohistochemical biomarkers in glioma. Multiple molecular biomarkers have been identified from the tumor, including isocitrate dehydrogenase 1 and 2 (IDH1/2), codeletion of chromosome arms 1p and 19q (1p/19q codeletion), and O-6-methylguanine-DNA methyltransferase (MGMT), which play important roles in patient stratification, risk group definition, and treatment response prediction, among others [4]. Tissue specimens obtained through a highly invasive method pose significant clinical risks. Furthermore, repeated tumor tissue sampling is completely impractical in clinical practice. Postoperative treatment options and therapy response monitoring are now solely based on the sequential examination of contrast-enhanced magnetic resonance imaging (MRI), which is assessed using the modified RANO criteria [5, 6]. Thus, unlike other tumors, no confirmed circulating biomarkers have yet been integrated into glioma diagnosis and treatment. MRI, as a standard imaging modality for glioma, is effective but can be misleading due to hysteresis and pseudoprogression. Early-stage glioma relapse cannot be easily monitored using only MRI-based detection. Therefore, there is an urgent need to develop a widely accessible and minimally invasive method for tracking glioma. Glioma progression is monitored using tumor-based circulating biomarkers as an additional parameter. In some cases, when tumor recurrence is uncertain, additional detection would be extremely valuable in aiding clinical decision-making.

Fibroblast activator protein is a membrane protease that is found in cancer-associated stromal fibroblasts and contributes to tumor progression but is absent or insignificant in most normal tissues [7–9]. Immunohistochemical studies on extracranial tumor tissues revealed that high FAP expression predicted a poor prognosis, implying that it plays an important role in the tumor [10]. Histopathological studies revealed that FAP expression was elevated in gliomas, particularly in mesenchymal subtypes [11]. While FAP has been studied as a biomarker in many cancer types, there have been no reports on monitoring glioma progression in longitudinal sequential serum FAP.

In the study, we looked for the serum marker FAP and evaluated its potential for monitoring glioma progression. Based on these findings, we conclude that combining serum FAP with MRI examination could improve the accuracy of tumor progression monitoring in clinical practice.

Patients

From February 2020 to May 2021, 87 glioma patients (47 males and 40 females, median age 48.2 years, range 18-74 years) were recruited for this study at the Affiliated Tumor Hospital of Xinjiang Medical University, the Third Affiliated Hospital of Zhengzhou University, and the Sun Yat-Sen University Cancer Center. These patients met the following inclusion and exclusion criteria: no combined tumors other than gliomas, age >18 years, no cancer history, and no prior anti-cancer therapy before blood collection. Following tumor removal, all patients received standard care. Glioma was classified using the current World Health Organization (WHO) Classification Criteria. All patients were diagnosed using pathological examination and histological specimens were confirmed by two independent experienced pathologists. Clinical characteristics were collected from the medical records. All research methods and experiments were conducted under the applicable regulations. The study was authorized by the medical ethics committee (SL-B2022-567-01). Individual participants or their family members provided written informed consent.

Blood sample collection

Blood samples from 87 patients with glioma were acquired from the cubital vein and incubated in 3 ml tubes with ethylene-diamine tetra acetic acid dipotassium salt, among the 33 patients with high-grade gliomas recruited to collect at least two peripheral venous blood samples consecutively during adjuvant chemotherapy. All of these samples were rested for 30 minutes at room temperature before being centrifuged at 3500 rpm at 4℃ for 10 min to separate the serum. The supernatants were collected and aliquoted into 250 μl cryo-tubes, which were then stored in liquid nitrogen until the FAP antigen level was determined using ELISA.

ELISA for blood samples

The plates were coated with 100 ng of recombinant FAP extracellular protein per well and incubated overnight at 4℃. After blocking the plates for 2 hours at room temperature with 300 μl blocking buffer (10 mM pH 7.4 PBS with 15% goat serum), the serum specimens were added to the wells at 37℃ for 1 h and washed 5 times. Another 1 hour at 37°C was spent incubating 100 μl of diluted HRP-labeled goat anti-human IgG antibody (Promega, USA). The plates were washed 3 times with the washing buffer before being treated with 100 μl TBM per well for 15 minutes at 37℃ and 50 μl 2M H₂SO₄ to block the response. The optical density of each well within 5 minutes was determined using a microplate reader set to 450 nm.

Immunohistochemistry (IHC) on human glioma tissue

IHC was conducted according to the manufacturer's instructions to detect FAP expression in glioma tissue. Briefly, after sectioning 0.5-μm-thick formalin-fixed paraffin-embedded (FFPE) tissue specimens, the slides were deparaffinized and rehydrated using progressive ethanol gradients. High-temperature antigen extraction was conducted in 10 mM/ml citrate buffer (pH 6.0) for 30 min. Endogenous peroxidase was quenched twice for 15 minutes with 3% hydrogen peroxide. Primary FAP-specific antibody (Promega, USA) was incubated for FAP staining in glioma slides. Finally, two neuropathologists counterstained, viewed, and photographed the slides.

MR image examination

All patients in the study had preoperative and postoperative regular MRI scans. After each postoperative FAP test venous blood collection, a matching multimodal MRI examination was available. The same multiplex scanner model, the protocol for acquisition, and reconstruction software were used for these patients. All MRI examinations were performed with contrast agents injected and were reviewed retrospectively. Two imaging specialists with more than 10 years of experience performed an independent analysis. Disputed results were resolved through group discussion following relevant guidelines and consensuses. The radiological doctors were aware that the tumors had been pathologically diagnosed as gliomas, but they were unaware of the patient’s molecular neuropathology and treatment information. Tumor volumes were automatically calculated using computer-aided planimetric software.

Data analyses

GraphPad Prism (Version 8.2.1) software was used to analyze FAP-level differences between pre-operation and post-operation, as well as differences between chemotherapy time points. The joint relationship between FAP level and tumor status (progression vs stability) was investigated in the pooled dataset.

Serum FAP is increased in the majority of human gliomas

The scatter plot depicted the preoperative and postoperative levels of serum FAP in the 87 patients, demonstrating that the relative level of serum FAP was distinct in various histopathological grades (Fig. 1Ⅰ-Ⅱ). The findings demonstrate an increase in serum FAP in most high-grade gliomas. Serum FAP levels were compared across pathological findings and molecular pathology. FAP level increased significantly with tumor grade, as shown in Fig. 1Ⅰ and Fig. 1 Ⅱ. Serum FAP levels generally decreased three days after surgery compared to preoperative levels (Fig. 1 Ⅱ). Based on the molecular phenotype, the level of serum FAP in different grades of gliomas has distinct characteristics. In terms of IDH mutation, FAP concentration was slightly lower in patients with IDH-mutant glioma compared to the IDH-wildtype (Fig. 1 Ⅲ). In the former, FAP concentrations were higher in grade 2 and grade 3 gliomas, while serum FAP levels were higher in grade 4 gliomas in the latter (Fig. 1 Ⅲa, b, c). Serum FAP levels were significantly lower in glioma patients with 1p/19q codeletion than in patients with 1p/19q non-deletion, and this difference was especially noticeable in patients with grade 4 glioma (Fig. 1 Ⅲd, e, f). Regardless of MGMT promoter methylation status, FAP levels were high in both MGMT-methylated and unmethylated gliomas at all grades. In patients with grade 2 and 3 gliomas, FAP levels were lower in patients with MGMT unmethylation than in patients with MGMT methylation. While serum FAP levels in grade 4 glioma patients show no discernible differences between methylated and unmethylated gliomas (Fig. 1Ⅲ g, h, i). However, there was significant FAP expression heterogeneity among identical graded gliomas (Fig. 1 and Table 1).

FAP expression in glioma tissues

Four glioma patients' paraffin-embedded tissues were available (Fig. 2 Ⅰ). The 4 FFPE specimens were histologically verified as gliomas (Table 1). The 4 FFPE specimens were histologically confirmed to be gliomas (Table 1). The intensity of FAP staining within the main tumor parenchyma corresponded to the level of serum FAP in these patients. Fig. 2 ⅠⅠ shows four selective IHC examples that show FAP is uniformly limited to the main tumor parenchyma. FAP was found in these tumors in two distinct patterns, as shown in Fig. 2 ⅠⅠ. To varying degrees, all four specimens had FAP-positive fields, with the vast majority of samples showing strong FAP staining predominantly localized in the fibrotic stromal bands (Fig. 2 ⅠⅠ). We also discovered a difference in FAP expression between GBM and grade 2 and 3 glioma. In IDH-Wildtype diffuse astroglioma, FAP-positive cells were extremely scarce.

Blood FAP level and its relation to MR image

A craniocerebral MR image scan and a blood draw for the FAP test were performed on the same day. It's worth noting that all of the cases had FAP expressions. Furthermore, when matched pairs of blood specimens from the 33 patients were compared for serial detection of serum FAP, the level of FAP was found to be positively related to tumor volume on MR images. To determine whether serum FAP fluctuation could be representative of glioma variation during treatment, serial serum samples from the 33 patients were obtained for FAP testing (Fig. 3 Ⅰ). Serum FAP levels were found to rise with tumor progression and to fall with chemotherapy. When the tumor is stable, there is no significant fluctuation in serum FAP. There was a minimal or present lesion in the surgical area in all 33 cases. We discovered a significant relationship between serum FAP concentration and tumor volume (Table 2). Three representative patients with varying degrees of tumor progression or elimination were chosen as models. Their intracranial lesions were identified using an MRI scan and brain tumor burden was calculated using computer-aided planimetric analysis. Most importantly, serum FAP levels decreased with therapy response and increased with tumor progression (Fig. 3 ⅠⅠ). Because the MRI examination and clinical symptoms were inconsistent, adding a blood FAP test can indirectly confirm invisible tumor progression. During follow-up after comprehensive treatment, serum FAP was higher in the presence of clinical signs of tumor progression than in the absence of clinical symptoms, while imaging examination did not differ significantly.

Precise diagnosis, to an extreme, can improve patients’ benefit from current treatment options. The identification of true progressive glioma remains a major challenge. Serum tumor markers monitoring is an ideal modality for patients with glioma because it is minimally invasive and safe. Based on this, we discovered evidence that serum-derived FAP from glioma patients can be used to detect the disease. Monitoring patients' response to treatment is critical but difficult in most cancers, particularly glioma, the most aggressive form of primary brain tumor. Currently, diagnosis and therapeutic response of gliomas are prevailingly evaluated by neuroimaging. However, tumors that are treated with surgery and chemoradiotherapy frequently enlarge on serial MRI visits, indicating progression versus radiation necrosis (also known as pseudoprogression). MR image or CT examination is an intuitive but sometimes deceptive approach that results in suboptimal precision.

Serum tumor marker detection has recently emerged as an emerging diagnostic candidate in glioma [12]. Generally, image logical examination’s accuracy in judging gliomas after therapy is partly limited, whereas serum tumor markers can fully replenish the deficiency, sparing patients suffering from reoperation [13, 14]. Tumor biomarkers in circulating liquid would thus be useful as tracers that could aid in diagnosis and contribute to the evaluation of patients' therapeutic effects. Circulating proteins released by tumor cells or cancer-associated cells have recently been identified as potential biomarkers for glioma, whereas existing markers show insufficient sensitivity or patient coverage for broad clinical applicability [15]. So far, little progress has been made in developing effective blood-based methods for tracking glioma. Though molecular and histological pathology based on tissue samples could provide accurate diagnosis and distinguish tumor markers for prognostic prediction, fluid-based tumor markers provide a minimally invasive approach for monitoring glioma without sampling tumors, despite its heterogeneity and evolution [16, 17]. In the current study, the potential diagnostic value of serum FAP detection as a marker was investigated in conjunction with tumor images. FAP is produced by human cancer-associated fibroblasts (CAFs) in tumors such as glioma. FAP, a transmembrane serine protease, is highly expressed in many tumors but completely absent in normal tissues [18, 19]. FAP has been identified as an independent biomarker associated with a poor prognosis in a growing number of cancers [20–23]. The presence of proangiogenic FAP in CAFs has been reported [9, 12, 24] which is consistent with our findings.

CAFs in cancers cause FAP accumulation and, as a result, an increase in serum FAP concentration. Some researchers discovered that FAP concentrations in glioma patients are significantly higher [25]. According to the literature, the FAP level in grade 2 gliomas is generally lower than that of patients with grade 3 and 4 gliomas, indicating that high-grade gliomas are associated with a high level of FAP expression [26]. To the best of our best knowledge, the dynamic serum FAP test has not been reported as a glioma detection index. Given the scarcity of research into blood FAP for glioma trace, dynamic monitoring of tumor markers for clinical application should be investigated. In comparison to an MRI examination, this procedure is less invasive, more accessible, inexpensive, and more convenient. In this regard, it would be extremely interesting for future studies to continuously track gliomas using serum FAP.

To investigate the relationship between serum FAP concentration and tumor features, we examined serum FAP levels and their relationship to image findings. In this study, serum FAP levels in preoperative gliomas were significantly higher than those in postoperative patients, indicating that serum FAP levels are positively related to tumor burden. FAP levels were significantly higher in patients with tumor progression than in those without recurrent glioma, indicating that a blood tumor marker of glioma effectively contributes to early diagnosis with high sensitivity. FAP expression in gliomas promotes tumor progression, though serum FAP levels vary. FAP-positive cells in immunohistochemical tests are spindle-shaped, fibroblast-like cells, which is consistent with our findings in gliomas [27]. Several studies on stromal cells such as CAFs in gliomas discovered FAP expression in neoplastic glial cells [28]. FAP is selectively expressed by CAFs and pericytes but not by tumor cells in the vast majority of human solid cancers [29]. The presence of prominent FAP staining in fibroblasts surrounding the tumor cells and minimal or absent expression in adjacent normal tissue was directly observed. Due to its highly selective distribution in tumors, FAP served as a biomarker of reactive CAFs [29]. The study found reported serum FAP expression in human solid tumors [29]. According to our findings, serum FAP level is positively associated with glioma grade and molecular state. Several studies in various cancers discovered that a significantly lower FAP level was associated with cancer status [30, 31]. The phenomenon was interpreted as a systemic response to tumor development [17, 32]. The homologous phenomenon was not observed in glioma.

After surgery and/or when combined with subsequent chemoradiotherapy, the disease is primarily assessed by MRI, and it is difficult to reliably distinguish tumor progression from radiation necrosis during certain periods. Although tissue biopsies are necessary for accurate diagnosis and molecular profiling, they only represent a static snapshot that cannot serially reflect variation in the mutational spectrum, microenvironment, and heterogeneity evolution. Tumor volume is closely related to the blood FAP levels, which may be useful for treatment strategy. FAP promotes posttreatment glioma invasive growth, indicating the presence of active tumor cells [10]. Even if no obvious mass is visible on the MR image, FAP expression may serve as a tracer.

MRI examination analysis confirmed the upregulation of FAP expression in gliomas. Exploration of the source of FAP found in blood samples will help us better understand it as a protein biomarker. Until now, a craniocerebral MRI scan has been recommended as a glioma examination modality. Dynamic serum FAP convincingly compensates for MRI deficiency in distinguishing radiation necrosis from tumor progression. Serial serum FAP test results are combined with neuroimaging to improve the accuracy of early diagnosis for glioma recurrence, indicating that the tumor marker combined with imaging is a viable modality in the clinical diagnosis of glioma. Recurrent gliomas are difficult to detect in their early stages. Serum FAP gradually increased with tumor space occupancy on MRI in our study, indicating that multiple types of cells associated with glioma progressions, such as parenchyma cells, mesenchymal cells, or endothelial cells, may promote this protein production.

In the current study, we identified and characterized FAP levels in the serum of glioma patients and compared them to MRI tumor burden assessments. Our findings show that serum FAP levels increased dramatically with tumor progression, implying that serum FAP can aid in the diagnosis of glioma and serve as a reference for tumor malignancy. Our findings also show that serum FAP levels vary significantly between gliomas, but are higher in a large proportion of higher-grade gliomas than lower-grade gliomas. Simultaneously, serum FAP concentrations decreased significantly in patients without tumor recurrence after effective treatment. While serum FAP levels significantly increased with larger recurrent tumor volume, serum FAP levels fluctuated with tumor condition. Because all of our analyses are based on longitudinal variations in serum FAP level, these serial assessments confirmed that serum FAP can be used to assess disease status. Another intriguing finding is that different serum FAP concentrations have a suggestive role in the molecular pathological subtypes of glioma. The relationship between serum FAP levels and MGMT promoter methylation status, on the other hand, is not as clear as that with other molecular statuses such as IDH and 1p/19q. We did not search for a direct link between MGMT status and FAP expression in the literature. In some cases in our study, serum FAP levels fluctuated while MRI assessments remained stable. This could be due to MRI's limited sensitivity in distinguishing small masses in tumor size, which necessitates further confirmation in a larger cohort.

Taken together, we investigated the potential of serum-derived FAP from glioma patients to serve as a biomarker for tumor progression. Our findings clearly show that dynamic detection of serum FAP is a simple method for determining treatment response and tumor status. These findings suggest that serum FAP may be a potentially reliable biomarker for disease monitoring in the context of glioma, which is critical for the timely and accurate assessment of therapeutic effects. Serum-derived FAP from glioma patients, combined with standard MRI assessment, significantly improves tumor progression monitoring.

Author contributions

Conceptualization: XSY, PFC, ZQZ, JZ; Writing—original draft preparation: PZ; Formal analysis: RXX; Investigation: HL, XMC; Methodology: XMP, JQL; Data curation: HBL; Validation: QYY; Supervision, project administration, funding acquisition and writing—review and editing: JZ; All authors approved the final manuscript.

Funding This study was funded by Natural Science Foundation of Guangdong Province, grant number 2022A1515012539.

Data availability

The data presented in this study are available on request from the corresponding author. All raw data have been uploaded and locked onto Research Data Deposit with an RDD number.

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional research ethics board of Sun Yat-Sen University Cancer Center ( (SL-B2022-567-01)).

Informed Consent Statement Written informed consent has been obtained from the patients or their family numbers to publish this paper.

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Table 1 Clinical and pathological characteristics of four gliomas

Patients	Age (years)	Gender	Diagnosis	Localization	Serum FAP	IDH mutation (Y/N)	1p\19q co-del (Y/N)	MGMTpm status
1	62	M	DA	RTL	0.99	N	Y	N
2	61	M	GBM	LTL	5.75	N	N	N
3	33	F	AA	RTIL	1.33	Y	N	N
4	34	F	AO	LFL	2.87	Y	Y	Y

DA diffuse astroglioma, AA anaplastic astrocytoma, AO anaplastic oligodendroglioma, RTL right temporal lobe, LTL left temporal lobe, RTIL right temporal-insular lobe, LFL left frontal lobe, Y means IDH1 R132H Mutation, N means Wildtype, PM promoter methylation

Table 2 The correlation between serum FAP level and tumor volume during adjuvant chemotherapy

Patients	Age (years)	Gender	Diagnosis	FAP₁/ TV₁(cm³)	FAP₂/ TV₂(cm³)	FAP₃ / TV₃(cm³)	FAP₄ / TV₄(cm³)
1	39	F	GBM, IDH(-)	0.58 / 24.46	0.92 / 43.77	1.17 / 61.73	- / -
2	57	F	GBM, IDH(-)	2.83 / 4.69	1.11 / 3.62	- / -	- / -
3	72	F	GBM, IDH(-)	2.33 / 1.59	0.76 / -	0.74 / 0.38	1.2 / 0.9

TV tumor volume

No competing interests reported.

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