Abstract
Background
Advances in medicine lead to an increase in the number of patients with concurrent heart disease and cancer. We investigated the effect of cardiac surgery under cardiopulmonary bypass (CPB) on the blood levels of growth factor cytokines, and assessed whether it might affect the proliferation of pancreatic cancer cells.
Methods
Ten consenting patients undergoing elective cardiac surgery with the use of CPB under general anesthesia. We obtained patients’ serum at each of the following time points: between median sternotomy and before activating CPB (pre-CPB), and after activating CPB (post-CPB). Growth factor cytokines in plasma samples were analyzed using cytokine array. Proliferation assay was performed using pancreatic cancer cells (PANC-1 and PK-1) incubated in culture medium containing patients’ serum at a concentration of 30%. The levels of cytokines and proliferation of cancer cells were compared between pre-CPB and post-CPB samples.
Results
Plasma and serum from eight patients were analyzed. PANC-1 and PK-1 cells proliferated significantly more following incubation with post-CPB (125%, P = 0.014 and 120%, P = 0.030, respectively) than pre-CPB samples. The following cytokines were significantly increased post-CPB compared to pre-CPB: amphiregulin (42 fold), basic fibroblast growth factor (5 fold), heparin binding-epidermal growth factor (9199 fold), hepatocyte growth factor (9 fold), insulin-like growth factor-binding protein (IGFBP)-1 (11 fold), IGFBP-4 (15 fold), insulin-like growth factor-2 (2 fold), macrophage colony-stimulating factor (2 fold), neurotrophin-4 (10 fold), transforming growth factor beta-3 (2 fold), vascular endothelial growth factor (VEGF)-A (3 fold), and VEGF receptor 2 (3 fold).
Conclusions
These results suggest that cardiac surgery with CPB increases the plasma levels of several growth factors, thus potentially promoting pancreatic cancer cell proliferation, as seen in the in vitro study using serum from non-cancer patients.
Trial registration
registration number UMIN000053046, date of registration December 12th, 2023.
Keywords: Cardiopulmonary bypass, Cytokine, Growth factor, Pancreatic cancer, Cardiac surgery, Cardiovascular anesthesia
Introduction
Advances in medicine have reduced cancer mortality and increased patient survival, including in the aged, leading to an increase in the number of patients with concurrent heart disease and cancer [1]. However, the risk of fatal heart disease increases with time for almost all cancer survivors [1]. In patients who require both cancer surgery and cardiac surgery, the decision regarding which surgery to perform first is at the discretion of the hospital and anesthesiologist.
Cardiopulmonary bypass (CPB) is performed during many cardiovascular surgeries. The use of CPB is known to increase the proliferation of inflammatory cytokines, such as interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α. [2, 3] Previous reports have demonstrated an increased incidence of skin melanoma and lung cancer in patients who undergo CPB, compared to off-pump open heart surgery. [4] Additionally, the serum of patients who have undergone cardiovascular surgery using CPB reportedly has reduced inhibitory effects on lung cancer cell proliferation. [5] However, several studies that compared blood samples before and after surgery, surmised that not only CPB, but also surgical invasion and anesthesia affect cancer cell proliferation.
Pancreatic ductal adenocarcinoma (PDAC) is the third overall leading cause of cancer-related mortality in the United States, and the poor prognosis associated with this disease is attributed to its early systemic spread and aggressive local growth [6]. In addition, the 5-year survival rate is around 10%, and the postsurgical 5-year survival rate is approximately 20%. [7] In resectable cases, surgical therapy remains the mainstay for improving prognosis. [6] However, due to high surgical invasiveness, cardiac surgery may be prioritized when sever cardiac disease is present. In such cases, immunological influence from CPB may also potentially affect the prognosis of pancreatic cancer. To our best knowledge, there is no immunological data available to determine the surgical approach.
Hence, we hypothesized that cardiac surgery under CPB might alter the blood levels of various cytokines, such as growth factors, thus potentially affecting pancreatic cancer cell proliferation. Here, we evaluated plasma levels of growth factors in serum from patients who underwent cardiac surgery under CPB, and the effect of serum obtained before and after CPB on in vitro pancreatic cancer cell proliferation to assess the effect of CPB on pancreatic cells.
Methods
Study design
This prospective in vitro study was approved by the clinical research ethics committee on October 20th, 2023 (RK-230912-6) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment with the University Hospital Medical Information Network (registration number UMIN000053046, Date of registration: December 12th, 2023). The study followed the Strengthening the Reporting of Observational Studies in Epidemiology Statement (STROBE statement). This study was conducted according to the principles of the Declaration of Helsinki.
Study population
Patients aged 20–79 years old undergoing elective cardiac surgery, such as heart valve replacement or repair, under general anesthesia and CPB, were enrolled in the study. We excluded patients who were American Society of Anesthesiologists physical status class ≥ IV, and those with immunological abnormalities, such as systemic infection, severe renal or liver failure, uncontrolled diabetes mellitus (HbA1c ≥ 8.0%), a medical history of cancer, or receiving steroids. In addition, patients receiving a second pump run were excluded to standardize the effects of CPB.
Anesthesia and cardiopulmonary bypass management
After preoxygenation, anesthesia was induced using propofol, fentanyl and remifentanil. All patients received intravenously cefazolin 1 g within 30 min of surgery. Tracheal intubation was facilitated with rocuronium. Anesthesia was maintained using sevoflurane or propofol by the anesthetist in charge. In addition, patients were administered 1 g tranexamic acid pre- and post-CPB. The right radial artery catheter was used for measurement of arterial pressure in all patients.
Initiation of CPB was preceded by the administration of heparin (initial dose 300 units/kg), ensuring that the activated clotting time was longer than 480 s during CPB. The CPB circuit included a centrifugal pump (SORIN REVOLUTION® Centrifugal Blood Pump; LivaNova Japan K.K., Tokyo, Japan) and heparin-coated membrane oxygenator (TERUMO CAPIOX® FX25 Advance Oxygenators with Integrated Arterial Filter; TERUMO Co., Tokyo, Japan). The prime for the CPB circuit consisted of crystalloid fluid (1000–1500 ml) and 500 ml of a 6% hydroxyethyl starch solution. Cardiac arrest was achieved using cold (4 °C) blood cardioplegia, consisting of a crystalloid solution (containing 10 mEq potassium chloride and 15% mannitol) and the patient’s blood. Moderate hypothermia (32–34 °C) was maintained during CPB.
Collection of samples
Blood samples (10 ml) were routinely collected at each of the following time points: 1) between median sternotomy and the use of CPB (administration of heparin) (pre-group) from the patient’s right radial artery catheter, and 2) after the use of CPB (post-group) from the CPB circuit. Of the collected blood samples, 1 ml was collected in a blood collection tube with heparin for cytokine assay (Becton Dickinson Co., Ltd., Tokyo, Japan), and the remaining 9 ml was put into a separate blood collection tube (Becton Dickinson Co., Ltd., Tokyo, Japan) and centrifuged at 1200 × g for 10 min. The resulting plasma and serum were stored at -80 °C until further analyses.
Cytokine antibody array and proliferation cell assay
For assessment of the effect of CPB on cytokine levels, we performed laboratory tests, in which plasma samples collected at the two time points were analyzed using a RayBio® Growth Factor for Human Cytokine Antibody Array (RayBiotech, Inc., Norcross, GA, USA) according to the manufacturer’s protocol.
For evaluation of the effect of CPB on pancreatic cancer cell proliferation, we performed an in vitro study using human pancreatic carcinoma cell lines, PANC-1 [8] and PK-1 [9]. For this, PANC-1 and PK-1 cells, obtained from the RIKEN BioResource Research Center (Tsukuba, Japan), were cultured in Dulbecco’s minimum essential medium (D-MEM), supplemented with 10% heat-inactivated fetal calf serum, 1% penicillin and streptomycin, in a humidified atmosphere of 95% air and 5% CO2 at 37°C.
Thereafter, 100 µl of a single cell suspension of the two cell lines in culture medium containing patients’ serum at a concentration of 30% were applied to each well of a 96-well microplate (7 × 103 cells/well) for assay.[5] The cells were incubated for 48 h. Thereafter, an MTS assay (Promega K.K., Tokyo, Japan) was conducted to evaluate cell proliferation, with absorbance measured at 490 nm using a microplate reader (Infinite® 200PRO series; FUJIFILM Wako, Tokyo, Japan), in triplicate.
Study outcomes
The primary outcome of this study was the effect of CPB on pancreatic cancer cell proliferation. Secondary outcomes were the effects of CPB on growth factor cytokines.
Sample size and statistical analysis
Based on previous comparable studies [10–12], we estimated that a sample size of eight patients would be required to identify a significant difference. We, thus, set a sample size of 10 patients in anticipation of some loss due to dropout. We used the Kolmogorov–Smirnov test to determine whether data showed normal distributions. The paired t-test was used for parametric data and Wilcoxon signed-rank test was used for non-parametric data to analyze differences in outcomes between the two groups. All statistical analyses were performed using EZR (Easy R) version 1.64 (Jichi Medical University Saitama Medical Center, Saitama, Japan). [13] Values of P < 0.05 were considered indicative of statistical significance.
Results
Descriptive data
A total of 10 patients who underwent cardiovascular surgery under CPB were enrolled in this study between December 2023 and July 2024, among whom two patients were excluded because of failure to collect blood samples (n = 1) and withdrawal of consent to participate (n = 1). As a result, eight patients were included in the final analyses. The patient characteristics are shown in Table 1.
Table 1.
Patient characteristics
| Sex (male / female) | 4 / 4 |
| Age (years) | 61 ± 10 |
| Height (cm) | 161 ± 10 |
| Body weight (kg) | 67 ± 5 |
| Operation (min) | 270 ± 69 |
| Anesthesia (min) | 363 ± 74 |
| Cardiac-pulmonary bypass (min) | 125 ± 25 |
| Aortic cross clamping (min) | 90 (84–123) |
| Remifentanil (mg) | 2.5 ± 1.2 |
| Fentanyl (mg) | 125 (100–200) |
| Hypertension (n) | 3 |
| Controlled diabetes mellitus (n) | 3 |
| AVR / MVR / MVP (n) | 3 / 1 / 4 |
| Creatine (mg/dL) | 0.91 ± 0.20 |
| White blood cell (103 cells/µL) | 5.49 ± 0.72 |
| C-reactive protein (mg/dL) | 0.15 ± 0.20 |
Data expressed as mean ± standard deviation, or median (inter-quartile range). AVR: aortic valve replacement, MVR: mitral valve replacement, MVP: mitral valve plasty
Primary results
The primary outcomes of the study are shown in Fig. 1. Both PANC-1 and PK-1 cells showed significantly greater proliferation following incubation with the post-CPB samples than with the pre-CPB samples (125%, P = 0.014 and 120%, P = 0.030, respectively).
Fig. 1.
Increased PDAC proliferation in vitro caused by CPB. The graph shows the absorbance (490 nm) of human PDAC cell lines (PANC-1, PK-1) following incubation with patients’ pre-CPB and post-CPB serum at concentrations of 30% for 48 h. The data were assessed in triplicate. PANC-1 (mean [SE]); P = 0.014, 95% CI [-0.23 to -0.04] (n = 8 each) by the paired t-test. PK-1 (mean [SE]); P = 0.030, 95% CI [-0.31 to -0.02] (n = 8 each) by the paired t-test. CPB: cardiopulmonary bypass, CI: confidence interval, PDAC: pancreatic ductal adenocarcinoma, SE: standard error
Secondary results
The secondary outcomes of the study are shown in Fig. 2. The following cytokines were significantly increased in the post-group compared to the pre-group: amphiregulin (AR) (42 fold, P = 0.016), basic fibroblast growth factor (bFGF) (5 fold, P = 0.033), heparin binding-epidermal growth factor (HB-EGF) (9199 fold, P = 0.036), hepatocyte growth factor (HGF) (9 fold, P < 0.001), insulin-like growth factor-binding protein (IGFBP)-1 (11 fold, P = 0.012), IGFBP-4 (15 fold, P = 0.013), insulin-like growth factor (IGF)-2 (2 fold, P = 0.049), macrophage colony-stimulating factor (M-CSF) (2 fold, P = 0.039), Neurotrophin (NT)-4 (10 fold, P = 0.001), transforming growth factor beta (TGFB)-3 (2 fold, P = 0.020), vascular endothelial growth factor (VEGF)-A (3 fold, P = 0.035), and VEGF receptor (VEGFR)2 (3 fold, P = 0.011).
Fig. 2.
Plasma cytokine levels in the pre-CPB (pre, n = 8) and post-CPB (post, n = 8) period and cytokine heatmaps for one representative patient. Data are presented as the means of two array spots. AR (median ± IQR); P = 0.016, by Wilcoxon signed-rank test; bFGF (mean [SE]); P = 0.033, 95% CI [-612.03 to -33.79], by the paired t-test; HB-EGF (median ± IQR); P = 0.036, by Wilcoxon signed-rank test; HGF (mean [SE]); P < 0.001, 95% CI [-2079.49 to -1123.56], by the paired t-test; IGFBP-1 (mean [SE]); P = 0.012, 95% CI [-4281.76 to -743.30], by the paired t-test; IGFBP-4 (mean [SE]); P = 0.013, 95% CI [-816.73 to -139.09], by the paired t-test; IGF-2 (mean [SE]); P = 0.049, 95% CI [-1634.65 to -2.77], by the paired t-test; M-CSF (median ± IQR); P = 0.039, by Wilcoxon signed-rank test; NT-4 (mean [SE]); P = 0.001, 95% CI [-1008.33 to -393.85], by the paired t-test; TGFB-3 (mean [SE]); P = 0.020, 95% CI [-1416.26 to -163.68] by the paired t-test; VEGF-A (mean [SE]); P = 0.035, 95% CI [-1422.52 to -71.75] by the paired t-test; and VEGFR2 (mean [SE]); P = 0.011, 95% CI [-1372.29 to -256.61] by the paired t-test; AR: amphiregulin, bFGF: basic fibroblast growth factor, CPB: cardiopulmonary bypass, CI: confidence interval, HB-EGF: heparin binding-epidermal growth factor, HGF: hepatocyte growth factor, IGF: insulin-like growth factor, IGFBP: insulin-like growth factor-binding protein, IQR: inter-quartile range, M-CSF: macrophage colony-stimulating factor, NT: Neurotrophin, SE: standard error, TGFB: transforming growth factor beta, VEGF: vascular endothelial growth factor, VEGFR: vascular endothelial growth factor receptor
Discussion
The results of this study demonstrated that serum from patients who underwent cardiovascular surgery using CPB enhanced cell proliferation of human PDAC cell lines (PNAC-1 and PK-1) and increased plasma levels of the following growth factors: AR, bFGF, HB-EGF, HGF, IGFBP-1, IGFBP-4, IGF-2, M-CSF, NT-4, TGFB-3, VEGF-A and VEGFR2.
This finding of promotion of cancer cell proliferation with the use of CPB is consistent with the findings of a study that examined the proliferation of human lung cancer cell lines. [5] Our results additionally showed that various growth factors are increased by using CPB, which might be the mechanism explaining the promotion of cancer cell proliferation.
Studies have reported that NT-4 serves as a prognostic marker and a potential therapeutic target for breast, colorectal and gastric cancer. [14–17] IGFBP-4 is known to be adversely associated with prognosis in lung cancer patients [17]. Elevated IGF2 levels are also known to be associated with an increased risk of developing various cancers, including colorectal, breast, prostate and lung cancers [18]. The expression of the TGFB-3 is reportedly elevated in patients with a short survival time due to breast cancer [19]. In another study, bFGF was reported to induce N-cadherin expression, an adhesion molecule promoting migration in both human normal cells and pancreatic cancer cells. [20] Additionally, it is known that the use of CPB increases the proliferation of inflammatory cytokines, such as IL-6, IL-8 and TNF-α, [2, 3] promoting tumor growth. [21] Pro-inflammatory cytokines, including IL-6 and TNF-α, cause an elevation of HB-EGF, and overexpression of HB-EGF has been found in many types of cancers, such as ovarian, breast, gastric, and endometrial cancers. [22] Our results of increased proliferation of cancer cell lines following CPB were also in agreement with the cytokine kinetics.
A previous study in 18 children showed that increased HGF levels were associated with endothelial cell injury induced by CPB [12]. The present study also showed that HGF levels were increased by CPB in adult patients. In pancreatic cancer patients, elevated serum HGF levels have been reported to correlate with disease progression. [23] Moreover, cancer-associated fibroblasts (CAFs) produce HGF, and tumor cells secrete growth factors that upregulate HGF production in CAFs. [24] Thus, increased HGF levels might establish a dynamic tumor-host signaling program. AR enables regulatory T cells to promote a profibrotic and immunosuppressive functional state of CAFs. [25] A previous study has demonstrated that VEGF-A levels are increased through M-CSF-dependent mechanisms, and that M-CSF increases IGFBP-1 levels. [26] Our study also showed that M-CSF, VEGF-A and IGFBP-1 levels were increased by CPB. In addition, a recent study found that M-CSF enhanced in vitro prostate cancer growth. [27] The influence of M-CSF on macrophage differentiation tends to promote the differentiation of macrophages towards the M2-like phenotype, which is associated with tumor-promoting properties [28]. This supports tumor growth by suppressing anti-tumor immune responses and promoting tissue remodeling and angiogenesis, which are beneficial for tumor progression. [28] It is known that IGFBP-1 secreted by microglial cells in response to glioma-secreted M-CSF is probably the major source for tumor angiogenesis [26]. Furthermore, the angiogenic response to VEGFA is mainly mediated via activation of VEGFR2 [29]. Since tumor angiogenesis is essential for solid tumor progression, invasion and metastasis, antiangiogenic therapies, including bevacizumab and ramucirumab, which target the VEGF-A/VEGFR2 axis to prevent tumor growth, invasion, and metastasis, have been developed [30]. Therefore, it is predicted that the use of CPB will induce proliferation of M2-like tumor-associated macrophages (TAMs) and CAFs and angiogenesis in cancer patients, promoting cancer proliferation.
Our study has several limitations that should be kept in mind when interpreting the results. First, this was strictly an in vitro study and we did not investigate cytokine dynamics with the use of CPB in “actual” cancer patients. Therefore, we were unable to demonstrate that alterations of M2-like TAMs, CAFs and angiogenesis are caused by the use of CPB. Further investigations of tumor-bearing patients undergoing CPB are warranted. Additionally, the effect of CPB on the cancer microenvironment should be verified in vivo using animal cancer models. Second, although we demonstrated that CPB increases the plasma levels of growth factors, we did not investigate other cytokines, such as inflammatory cytokines and chemokines. Third, PANC-1 and PK-1 cell lines were cultured in medium containing patient’s serum at a concentration of 30%. The effect of growth factor may vary depending on their concentration, and therefore, the degree of cell proliferation may also change. Further investigation is required to clarity in this regard. Fourth, in the next phase of this study, we believe it is necessary to investigate how long the change in cell proliferation persists after CPB. Fifth, the effects of anesthetic methods, surgical procedures and perioperative medications may also be involved.
In conclusion, the present study could provide the results as our hypothesis that cardiac surgery under CPB increases the plasma levels of several growth factors and promotes pancreatic cancer cell proliferation in vitro.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for the English language review.
Author contributions
Seidai Katagiri: Conceptualization-equal, Data curation-equal, Investigation-equal, Visualization-equal, Writing-original draft-equal Tomoaki Itaya: Conceptualization-equal, Data curation-equal, Formal analysis-equal, Methodology-equal, Investigation-equal, Visualization-equal, Writing-original draft-equal, Writing-review and editing-equal Makoto Sano: Conceptualization-equal, Methodology-equal, Writing-review and editing-equal Naoto Kiuchi: Data curation-equal, Formal analysis-equal Yuta Toyoshima: Investigation-equal, Visualization-equal Shunichi Takagi: Investigation-equal, Conceptualization-equal. Takahiro Suzuki: Conceptualization-equal, Project administration-equal, Supervision-equal, Writing-review and editing-equal All authors read and approved the final manuscript.
Funding
Funding was received in the form of a grant from the Japan Society for the Promotion of Science KAKENHI (grant no. JP24K12060).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Seidai Katagiri and Tomoaki Itaya have contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.