Senchukova MA, Ishemgulov AT, Letuta SN, Saidler NV, Tagabilev DG. Changes in the metabolism of axillary lymph node cells as a predictor of regional metastasis in breast cancer. World J Exp Med 2026; 16(3): 125128 [DOI: 10.5493/wjem.125128]
Corresponding Author of This Article
Marina A Senchukova, Scientific and Clinical Center No. 3, Petrovsky National Research Centre of Surgery, Oktyabrsky Prospekt, 3, Moscow 108840, Troitsk, Russia. masenchukova@yandex.com
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Oncology
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Senchukova MA, Ishemgulov AT, Letuta SN, Saidler NV, Tagabilev DG. Changes in the metabolism of axillary lymph node cells as a predictor of regional metastasis in breast cancer. World J Exp Med 2026; 16(3): 125128 [DOI: 10.5493/wjem.125128]
Marina A Senchukova, Dmitry G Tagabilev, Scientific and Clinical Center No. 3, Petrovsky National Research Centre of Surgery, Moscow 108840, Troitsk, Russia
Azamat T Ishemgulov, Sergey N Letuta, Department of Biophysics, Orenburg State University, Orenburg 460018, Russia
Natalia V Saidler, Department of Pathology, Orenburg Regional Cancer Clinic, Orenburg 460021, Orenburgskaya Oblast’, Russia
Author contributions: Senchukova MA formulated the idea and aims of the study, wrote the first version of the manuscript and performed the analysis of the results and statistical processing of the results; Saidler NV made a significant contribution to the development of the study methodology, participated in the preparation of tables and figures; Ishemgulov AT designed and performed all the experiments with the determination of delayed luminescence of erythrosine (DLE) in breast tissue; Letuta SN upended the experiments to determine the DLE in breast tissues and participated in the discussion of the research results; and Tagabilev DG participated in the discussion of the obtained results and helped to revise the manuscript. All the authors wrote and approved the final version of the manuscript.
AI contribution statement: The authors did not use any AI tool in preparing this manuscript.
Supported by Russian Science Foundation, No. 23-25-00183.
Institutional review board statement: Ethical approval was obtained from the Ethics Committee of Orenburg State Medical University (No. 311, dated January 13, 2023).
Clinical trial registration statement: The study does not require registration as it does not meet the definition of a clinical trial.
Informed consent statement: All patients provided written informed consent to participate in the clinical study.
Conflict-of-interest statement: The authors (Azamat T Ishemgulov, Marina A Senchukova, Sergey N Letuta and Natalia V Saydler) declare the existence of a patent interest: "Method for detecting tumor tissue in surgical material for breast cancer." Patent number RU 2835219 C1 02/25/2025.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Corresponding author: Marina A Senchukova, Scientific and Clinical Center No. 3, Petrovsky National Research Centre of Surgery, Oktyabrsky Prospekt, 3, Moscow 108840, Troitsk, Russia. masenchukova@yandex.com
Received: July 1, 2026 Revised: August 3, 2026 Accepted: August 28, 2026 Published online: September 20, 2026 Processing time: 83 Days and 3.6 Hours
Abstract
BACKGROUND
Recent studies have shown that the delayed luminescence of erythrosine (DLE) indicators differs between tumor and nontumor breast tissue in patients with breast cancer (BC).
AIM
To study the features of metabolism of axillary lymph node (ALN) cells and their relationship with regional metastasis in BC patients.
METHODS
This prospective, single-center, observational cohort study included 69 patients with newly diagnosed BC. DLE indicators were measured for 152 ALNs. DLE decay kinetics were recorded using flash photolysis. A control circuit interfaced the analog measuring devices and digital data processing systems. Eighty-eight and 74 ALN samples were stained with antibodies against vascular cell adhesion molecule-1 (VCAM-1) and C-X-C motif chemokine receptor 4 (CXCR4), respectively. Statistical calculations were performed using Statistica version 12.0 software.
RESULTS
Singlet oxygen-sensitized delayed fluorescence (SOSDF) indicators were significantly lower, whereas phosphorescence and thermally activated delayed fluorescence indicators were significantly higher in ALNs with metastases than in those without metastases (P < 0.0001). Pronounced VCAM-1 expression in ALNs was significantly more common in patients with tumor grade 3 and human epidermal growth factor receptor 2 (HER2) overexpression and in patients with HER2-positive BC. Pronounced CXCR4 expression in lymph node (LN) follicles was detected significantly more often in patients with metastases in ALNs and with lymphovascular invasion. The intensity of delayed phosphorescence positively correlated with both VCAM-1 and CXCR4 expression in the LN follicles, and VCAM-1 expression in the LN follicles was negatively correlated with SOSDF and positively correlated with the duration of delayed phosphorescence.
CONCLUSION
These results indicate that metastatic LNs exhibit greater oxygen consumption by tumor cells and that changes in tumor cell metabolism are associated with increased CXCR4 and VCAM-1 expression in ALNs.
Core Tip: We studied the delayed luminescence of erythrosine indicators and the expression of vascular cell adhesion molecule-1 (VCAM-1) and C-X-C motif chemokine receptor 4 (CXCR4) in axillary lymph nodes (LN) from patients with breast cancer. The results indicated that metastatic LNs exhibit greater oxygen consumption by tumor cells and that changes in tumor cell metabolism are associated with increased CXCR4 and VCAM-1 expression in axillary LNs.
Citation: Senchukova MA, Ishemgulov AT, Letuta SN, Saidler NV, Tagabilev DG. Changes in the metabolism of axillary lymph node cells as a predictor of regional metastasis in breast cancer. World J Exp Med 2026; 16(3): 125128
In 2022, breast cancer (BC) was the second leading cause of cancer incidence worldwide and the fourth leading cause of cancer death worldwide[1,2]. In most countries, BC is the most frequently diagnosed cancer and the leading cause of cancer death among women. BC is a highly heterogeneous disease. Different molecular subtypes of BC differ in their clinical course, drug therapy efficacy, and prognosis. The presence of axillary lymph node (ALN) metastases not only significantly reduces patient survival but also affects the effectiveness of therapy, since the sensitivity of tumor cells to chemotherapy and targeted drugs may differ between the primary tumor and metastases[3-5]. Considering that changes in tumor cell metabolism affect tumor growth and the ability to metastasize, studying differences in the metabolism of normal and tumor cells is of interest for both the diagnosis and treatment of malignant neoplasms, as well as for assessing the prognosis of the disease and the effectiveness of treatment.
One of the key factors associated with changes in tumor cell metabolism is hypoxia. Under its influence, tumor cell metabolism is reprogrammed toward aerobic glycolysis, which not only allows them to survive under conditions of chronic hypoxic stress but also promotes the acquisition of more aggressive phenotypes characterized by an increased risk of metastasis and resistance to anticancer treatments[6,7]. Therefore, studying the mechanisms associated with tumor cell metabolism remains a pressing issue in modern oncology. Given that oxygen plays a key role in cellular respiration and energy production, the dynamics of changes in oxygen concentrations in different tissues provide important information about the characteristics of their metabolism[8,9].
One of the most effective methods for monitoring changes in oxygen concentration in tissues is studying the kinetics of the delayed luminescence of endogenous or exogenous photosensitizers[10]. Previously, analysis of the kinetic curves of delayed luminescence of erythrosine (DLE) revealed differences in oxygen consumption between normal and tumor tissues of the mammary glands of mice and patients with BC, which is associated with differences in the metabolism of these tissues[11,12]. Importantly, the molecular and metabolic characteristics of primary tumors associated with BC progression factors and sensitivity to drug therapy have been well studied[13,14]; however, studies examining these characteristics in ALNs are clearly insufficient. Therefore, the aim of this study was to investigate the indicators of DLE in the ALNs of patients with BC and their correlations with the expression of vascular cell adhesion molecule-1 (VCAM-1) and C-X-C motif chemokine receptor 4 (CXCR4), which, according to the literature, are also associated with the reprogramming of cellular metabolism[15-17].
MATERIALS AND METHODS
Patient characteristics
This study is a continuation of a prospective cohort study of BC progression factors, which included 148 patients with newly diagnosed BC who underwent radical surgery as the first stage of treatment[18,19]. Using a blind selection method, a total of 69 patients with newly diagnosed stage T1-T2 BC, aged 34 to 86 years (61.9 ± 11.7 years, median 61 years), were enrolled in this prospective, single-center cohort study. The inclusion criteria for the study were as follows: (1) Invasive ductal BC; (2) Disease stage T1-2N0-1M0; (3) Age over 18 years; and (4) Signed consent to participate in the clinical trial. The exclusion criteria were as follows: (1) Patients aged 18 years or younger; (2) Patients who received neoadjuvant therapy (chemotherapy, targeted therapy, or hormonal therapy), radiation therapy, corticosteroids or nonsteroidal anti-inflammatory drugs before surgery; and (3) Patients who refused to participate in the study. All patients included in the study underwent standard clinical and instrumental examinations to establish the stage of the disease, as well as histological and immunohistological examinations of tumor biopsy material to determine the molecular subtype of BC. The 8th edition of the TNM staging system was used for BC staging. The characteristics of the patients included in the study are presented in Table 1.
Table 1 Clinical and pathological characteristics of breast cancer patients.
Radical surgical treatment was performed in all patients at the Orenburg Regional Clinical Oncology Center from January 15, 2023, to June 30, 2023. Breast-conserving surgery was performed in 44 patients (63.8%), and radical mastectomy was performed in 25 patients (36.2%). All patients underwent ALN dissection (levels I-II). The study was conducted in accordance with the Declaration of Helsinki and internationally recognized guidelines. All patients provided written informed consent to participate in the clinical study. Ethical approval was obtained from the Ethics Committee of Orenburg State Medical University (Protocol No. 311 dated January 13, 2023).
Study of the DLE in ALNs
In the operating room, after surgical specimen removal, 2 to 4 ALNs [a total of 214 lymph nodes (LN)] were harvested within 15-20 minutes. DLE parameters were studied in 152 ALNs. This number of ALNs is sufficient to obtain statistically significant conclusions, as at the 95% confidence level, a 5% confidence interval (CI), a population size of 214, and a response rate of 14% (20 ALNs had metastases), the required sample size is 100 ± 1.6 LNs. The study design flowchart is shown in Figure 1.
ALNs intended for the DLE study were divided in half longitudinally. In the operating room, 1-2 mm-thick sections were taken from the incision surface and immediately placed in sterile Eppendorf tubes containing 1.5 mL of sterile medium 199. The tubes were stored in a refrigerator at 4 °C for 2 to 4 hours prior to the start of the study. Preliminary studies of the same samples were conducted at 2 hours, 4 hours, and 6 hours, and the results were stable.
DLE parameters were studied as follows: ALN samples were immersed in an aqueous solution (0.5 mmol/L) of erythrosine (Sigma-Aldrich, Switzerland) for 1 minutes and then washed with a sterile solution of 0.9% sodium chloride. Flash photolysis was used to obtain DLE kinetic curves. The second harmonic (532 nm) of an LQ-214 YAG (Nd3+) laser (Solar, Belarus) with a pulse duration of 15 ns and a power density of up to 1 MW/cm2 was used as the excitation source. Each stained sample was excited with a series of 10 pulses at a frequency of 10 Hz. Luminescence was recorded using an MDR-41 monochromator (Spektr, Russia) with an FEU-84-3 (Electronics and Communications, Russia) at wavelengths of 570 nm [for Singlet oxygen-sensitized delayed fluorescence (SOSDF) and thermally activated delayed fluorescence (TDF)] and 680 nm (for phosphorescence). Mathematica (Wolfram Research, United States) and OriginPRO (Origin Lab, United States) were used to process the experimental curves.
For each pulse train, 10 DLE decay curves were obtained. The metrics of the DLE decay curves in some samples changed during multi-pulse excitation. To characterize these changes, the parameters of the first curve were taken as unity, and the dynamics of the DLE parameters (intensity and duration) were evaluated from the first curve over the course of ten curves. Specifically, the SOSDF intensity (the initial portion of the delayed fluorescence decay curve) in some samples decreases during pulse excitation at a frequency of 10 Hz, tending toward a certain equilibrium value. DLE decay curves for ALN tissue and the change in the integrated intensity of SOSDF erythrosine in stained tissue during 10-pulse excitation are shown in Figure 2.
Figure 2 Kinetics of delayed fluorescence in a lymph node stained with erythrosine.
A: Kinetics of delayed fluorescence in a lymph node stained with erythrosine under multi-pulse excitation at a frequency of 10 Hz (curves for the first and tenth excitation pulses are shown); B: Kinetics of phosphorescence in a lymph node stained with erythrosine under multi-pulse excitation at a frequency of 10 Hz (curves for the first and tenth excitation pulses are shown); C: Change in the integral intensity of singlet oxygen-sensitized delayed fluorescence (SOSDF) of erythrosine in stained tissue during 10-pulse excitation (the integral intensity of SOSDF for the first pulse is taken as unity). SOSDF: Singlet oxygen-sensitized delayed fluorescence; DLE: Delayed luminescence of erythrosine.
Thus, the changes in the following DLE parameters over 10 pulses were characterized: Indicator 1: Change in the integral SOSDF intensity (the integral intensity of the curve after the 10th pulse divided by the integral intensity of the curve after the first pulse for delayed fluorescence); indicator 2: Change in the integral phosphorescence intensity; indicator 3: Rate of change in the integral intensity of SOSDF over 10 pulses (characterizes how quickly the intensity changes in Figure 2C, calculated from the equation for the approximating curve; indicator 4: Minimum equilibrium value of the integrated intensity of SOSDF during multipulse excitation with a frequency of 10 Hz (calculated from the equation for the approximating curve); indicator 5: Change in phosphorescence duration (phosphorescence duration after the 10th pulse divided by phosphorescence duration after the first pulse); and indicator 6: Duration of TDF.
Evaluation of VCAM-1 and CXCR4 expression in ALNs
Marker expression was assessed separately in the LN sinuses, LN follicles, LN cortex, and LN medulla. First, the number of sinuses and follicles in the LNs was determined at 100 × magnification. VCAM-1 and CXCR4 expression was assessed at 200 × magnification. Table 2 presents the algorithm for calculating marker expression.
Table 2 Evaluation of vascular cell adhesion molecule-1 and C-X-C motif chemokine receptor 4 expression in axillary lymph nodes.
VCAM-1
CXCR4
Marker expression in the LN sinuses
The number of sinuses
0: None
1: ≤ 15%
2: > 15%
The intensity of marker expression
0: No expression
0: No expression
1: Weak expression
1: Expression present
2: Moderate expression
3: Pronounced expression
Marker expression scores in LN sinuses
By multiplying the number of sinuses and intensity of marker expression (score range 0-6)
By multiplying the number of sinuses and intensity of marker expression (score range 0-2)
Marker expression in the LN follicles
Number of follicles
0: < 5% of the lymph node area
1: ≥ 5% and < 30% of the lymph node area
2: ≥ 30% of the lymph node area
The intensity of marker expression
0: No expression
0: No expression
1: Weak expression
1: Weak expression
2: Moderate expression
2: Moderate expression
3: Pronounced expression
3: Pronounced expression
Marker expression scores in LN follicles
By multiplying the number of follicles and intensity of marker expression (score range 0-6)
By multiplying the number of follicles and intensity of marker expression (score range 0-6)
Marker expression in the LN cortex
The intensity of marker expression
0: No expression
0: No expression
1: Weak expression
1: Weak expression
2: Moderate expression
2: Moderate expression
Marker expression in the LN medulla
The intensity of marker expression
0: No expression
0: No expression
1: Weak expression
1: Weak expression
2: Moderate expression
2: Moderate expression
Marker expression in metastases cells
Number of cells with marker expression
1: < 50% of cells
1: < 50% of cells
2: 50% or more of cells
2: 50% or more of cells
The intensity of marker expression
0: No expression
0: No expression
1: Weak expression
1: Weak expression
2: Moderate expression
2: Moderate expression
3: Pronounced expression
Marker expression scores in metastases
By multiplying the number of cells with marker expression and intensity of marker expression (score range 0-4)
By multiplying the number of cells with marker expression and intensity of marker expression (score range 0-4)
Figure 3 Examples of Vascular cell adhesion molecule-1 and C-X-C motif chemokine receptor 4 expression assessment in an axillary lymph node.
A: Assessment of the number of sinuses (2: > 15%) and lymphoid follicles (1: ≥ 5% and < 30% of the lymph node area) in the axillary lymph node; B: Assessment of vascular cell adhesion molecule-1 (VCAM-1) expression in the lymph node sinuses (0: No expression), lymph node follicles (0: No expression), lymph node cortex (0: No expression) and lymph node medulla (0: No expression); C: Assessment of C-X-C motif chemokine receptor 4 (CXCR4) expression in the lymph node sinuses (1: Weak expression), lymph node follicles (2: Moderate expression), lymph node cortex (1: Weak expression), and lymph node medulla (1: Weak expression); D: Breast cancer metastasis in the axillary lymph node (arrow); E: No VCAM-1 expression in tumor cells in the lymph node with metastasis; F: Weak CXCR4 expression in tumor cells in the lymph node with metastasis (A and D: Mayer’s hematoxylin and eosin staining; B and E: Staining with antibodies against VCAM-1; C and F: Staining with antibodies against CXCR4).
Statistical analyses
Statistica software version 12.0 was used for the statistical analyses. Depending on the normality of the distribution, the data are presented as the means ± SD or medians. The Kolmogorov-Smirnov test was used to assess the normality of the continuous data. Correlations between variables were assessed using nonparametric Spearman’s rank correlation (ρ) or Kendall's rank correlation (τ), depending on the type of variables. Continuous variables were compared using the Mann-Whitney test or median tests. Categorical variables were compared using the χ2 test. To assess the relationship between the expression of markers and the presence of metastases in the studied LNs, odds ratios (ORs) were calculated. Interobserver concordance of CXCR4 and VCAM-1 expression in LN follicles was assessed using positive percentage agreement (PPA), negative percentage agreement (NPA), and overall rate of agreement (ORA). The strength of agreement was calculated using Cohen’s kappa coefficient. After multiple testing was adjusted by the Bonferroni correction (α = 0.05/2), a significance level of ≤ 0.025 was considered to indicate statistical significance.
RESULTS
The values of the DLE indicators were analyzed in 152 LNs, including 103 normal LNs, 29 reactive LNs, and 20 LNs with metastases. The values of the DLE indicators depending on the nature of the changes in the ALNS are presented in Figure 4 and Table 3.
An analysis of the DLE indicator values depending on the type of LN examined revealed that the SOSDF (indicators 1, 3, and 4) and TDF (indicator 6) values in LNs with metastases were significantly lower than those in normal and reactive ALNs, whereas delayed phosphorescence (indicators 2 and 5) was significantly greater in LNs with metastases. The DLE indicator values did not differ significantly between normal and reactive LNs, with the exception of indicator 2, which was significantly lower in reactive LNs than in normal LNs.
VCAM-1 expression in the ALNs
VCAM-1 expression was studied in 88 ALNs, including 52 normal LNs, 10 reactive LNs, and 16 LNs with metastases. The values of VCAM-1 expression in ALNs depending on the nature of the LNs are presented in Figure 5 and Table 4.
Figure 5 Vascular cell adhesion molecule-1 expression scores according to the nature of the changes in axillary lymph nodes.
VCAM-1: Vascular cell adhesion molecule-1; LN: Lymph node.
Table 4 Vascular cell adhesion molecule-1 expression scores according to the nature of the changes in axillary lymph nodes.
Analysis of VCAM-1 expression scores in ALNs according to the nature of the LNs revealed that VCAM-1 expression scores in LN follicles and in the LN medulla were significantly greater in LNs with metastases than in normal LNs. VCAM-1 scores of 2 or more in LN follicles were found in 10 of 16 LNs with metastases and in 19 of 62 LNs without metastases (OR = 4.6491; 95%CI: 1.4872-14.5335; P = 0.0082). Interestingly, compared with that in normal LNs, VCAM-1 expression in LN follicles was significantly greater in reactive LNs (P < 0.0001).
CXCR4 expression in the ALNs
CXCR4 expression was studied in 74 ALNs, including 56 normal LNs, 6 reactive LNs, and 12 metastatic LNs. CXCR4 expression scores in ALNs according to the type of LN are presented in Figure 6 and Table 5.
Analysis of CXCR4 expression scores in the ALNs according to the nature of the changes in ALNs revealed that the CXCR4 expression scores in the follicles were significantly higher in the LNs with metastases than in the normal LNs (P = 0.0235). CXCR4 scores of 2 or more in LN follicles were found in 10 of 12 LNs with metastases and in 28 of 62 LNs without metastases (OR = 6.0714; 95%CI: 1.2277-30.0264; P = 0.0270). CXCR4 expression in the LN cortex was significantly higher in reactive LNs than in normal nodes (P = 0.0079) and in LNs with metastases (P = 0.0155).
Considering that pathological changes in tissues can influence the expression patterns of markers in draining LNs, we studied the correlations between DLE indicators and VCAM-1 and CXCR4 expression in ALNs and the clinical and pathological characteristics of patients with BC. The results of the correlation analysis between DLE indicators and the clinical and pathological characteristics of patients with BC are presented in Figure 7 and Table 6.
Figure 7 Heatmaps of correlations between indicators of delayed luminescence of erythrosine and clinical and pathological characteristics of patients with breast cancer.
+: Positive correlations; -: Negative correlations; BC: Breast cancer; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; IDC: Intraductal component; LVI: Lymphovascular invasion; PNI: Perineural invasion; PR: Progesterone receptor.
Table 6 Correlations between indicators of delayed luminescence of erythrosine and clinical and pathological characteristics of patients with breast cancer.
According to the obtained data, the SOSDF indicators (indicators 1, 3 and 4) were negatively correlated with N stage, tumor grade and the presence of lymphovascular invasion (LVI), whereas the delayed phosphorescence indicators (indicators 2 and 5) were positively correlated with N stage and the presence of LVI. The analysis revealed that the SOSDF indicators (indicators 3 and 4) were significantly lower and that the delayed phosphorescence indices were significantly greater in the N2-3 stages of BC than in the N0-1 stages, as well as in the presence of LVI than in its absence. In addition, the lowest values of the SOSDF indicators were noted for high-grade tumor malignancy (G3) and with a Ki67 index ≥ 40%, whereas the delayed phosphorescence indicators (indicators 2 and 5) were the highest for these BC characteristics. The data on the SOSDF indicators according to the BC characteristics are presented in Table 7.
Table 7 Values of the delayed luminescence of erythrosine in accordance with the clinical and pathological characteristics of breast cancer.
The results of the correlation analysis between VCAM-1 expression in ALNs and the clinical and pathological characteristics of patients with BC are presented in Figure 8 and Table 8.
Figure 8 Heatmaps of correlations between vascular cell adhesion molecule-1 expression in axillary lymph nodes and clinical and pathological characteristics of patients with breast cancer.
VCAM: Vascular cell adhesion molecule; +: Positive correlations; -: Negative correlations; BC: Breast cancer; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; IDC: Intraductal component; LN: Lymph node; LVI: Lymphovascular invasion; PNI: Perineural invasion; PR: Progesterone receptor.
Table 8 Correlations of vascular cell adhesion molecule-1 expression with the clinical and pathological characteristics of patients with breast cancer.
According to the obtained data, VCAM-1 expression in ALNs positively correlated with tumor progression factors such as tumor grade, human epidermal growth factor receptor 2 (HER2) status and the Ki67 index and negatively correlated with ER status. The strongest correlations with tumor progression factors were established for VCAM-1 expression in LN follicles (P < 0.001). To divide patients into groups with weak and pronounced VCAM-1 expression in ALNs, we constructed receiver operating characteristic (ROC) curves discriminating between VCAM-1 expression values in LNs with and without metastases. The area under the curve (AUC) for VCAM-1 expression in LN sinuses was 0.592 (95%CI: 0.434-0.708), and the cutoff was 2 (sensitivity = 0.5; specificity = 0.69). The AUC for VCAM-1 expression in LN follicles was 0.743 (95%CI: 0.642-0.844), and the cutoff was 2 (sensitivity = 0.737; specificity = 0.633). The AUC for VCAM-1 expression in the LN cortex was 0.538 (95%CI: 0.425-0.652), and the cutoff was 1 (sensitivity = 0.316; specificity = 0.755). The AUC for VCAM-1 expression in the LN medulla was 0.553 (95%CI: 0.43-0.675), and the cutoff was 2 (sensitivity = 0.474; specificity = 0.755). VCAM-1 expression in tumor cells was absent in 9 (56.3%), moderate in 6 (37.5%), and pronounced in 1 (6.2%) metastatic LN.
Pronounced VCAM-1 expression was significantly more common in all LN structures in patients with tumor grade 3 (G3) than in those with tumor grade 1-2 (G1-G2), in patients with HER2 overexpression than in those without HER2 overexpression, and in patients with HER2-positive BC subtypes than in those with HER-2-negative BC subtypes. In addition, pronounced VCAM-1 expression in LN sinuses was significantly more common in patients with a positive estrogen receptor status (ER+) than in those with a negative ER status (ER-). Pronounced VCAM-1 expression in LN follicles was significantly more common in patients over 60 years of age than in younger patients and in patients with a Ki67 index ≥ 40% than in those with a Ki67 index < 40%. The frequency of weak and pronounced VCAM-1 expression in ALNs according to the clinical and pathological characteristics of patients with BC is presented in Table 9.
Table 9 Frequency of weak and pronounced vascular cell adhesion molecule-1 expression in lymph nodes according to the clinical and pathological characteristics of patients with breast cancer, n (%).
The results of the correlation analysis between CXCR4 expression and the clinical and pathological characteristics of patients with BC are presented in Figure 9 and Table 10.
Figure 9 Heatmaps of correlations between C-X-C motif chemokine receptor 4 expression in axillary lymph nodes and clinical and pathological characteristics of patients with breast cancer.
+: Positive correlations; -: Negative correlations; CXCR4: C-X-C motif chemokine receptor 4; BC: Breast cancer; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; IDC: Intraductal component; LN: Lymph node; LVI: Lymphovascular invasion; PNI: Perineural invasion; PR: Progesterone receptor.
Table 10 Correlations of C-X-C motif chemokine receptor 4 expression with the clinical and pathological characteristics of patients with breast cancer.
According to the data obtained, the most significant (P < 0.001) positive correlations of CXCR4 expression were with N stage (for CXCR4 expression in LN follicles and the medulla), the presence of LVI (for CXCR4 expression in the LN medulla), PR status (for CXCR4 expression in the LN medulla), and the Ki67 index (for CXCR4 expression in the LN cortex). The correlations of CXCR4 expression in the LN cortex with age, tumor grade, and BC subtype (P < 0.01) and of CXCR4 expression in the LN medulla with LVI were also revealed. However, the correlations of CXCR4 expression in the LN sinuses and cortex with T stage were negative (P < 0.01). Weak and pronounced CXCR4 expression in tumor cells was detected in 6 (50%) and 6 (50%) LNs with metastases, respectively.
To divide patients into groups with weak and pronounced CXCR4 expression in ALNs, we constructed ROC curves discriminating between the CXCR4 expression values in LNs with and without metastases. The AUC for CXCR4 expression in LN sinuses was 0.594 (95%CI: 0.445-0.744), and the cutoff was 1 (sensitivity = 0.643; specificity = 0.4). The AUC for CXCR4 expression in LN follicles was 0.763 (95%CI: 0.656-0.871), and the cutoff was 2 (sensitivity = 0.857; specificity = 0.689). The AUC for CXCR4 expression in the LN cortex was 0.514 (95%CI: 0.393-0.636), and the cutoff was 1 (sensitivity = 0.643; specificity = 0.4). The AUC for CXCR4 expression in the LN medulla was 0.563 (95%CI: 0.499-0.677), and the cutoff was 1 (sensitivity = 0.902; specificity = 0.148). Pronounced CXCR4 expression in LN follicles was detected significantly more often in patients with metastases in ALNs than in those without metastases and in those with LVI than in those without it. Interestingly, pronounced CXCR4 expression in the LN sinuses, LN follicles, and LN medulla was significantly more common in patients with stage T1 disease than in those with stage T2 disease. Furthermore, pronounced CXCR4 expression in LN follicles was significantly more common in patients with a positive PR status than in those with a negative PR status. Pronounced CXCR4 expression in the LN cortex and LN medulla occurred significantly more often in patients who were 60 years of age and older than in younger patients did. The frequency of weak and pronounced VCAM-1 expression in ALNs according to the clinical and pathological characteristics of patients with BC is presented in Table 11.
Table 11 Frequency of weak and strong C-X-C motif chemokine receptor 4 expression in axillary lymph nodes according to the clinical and pathological characteristics of patients with breast cancer, n (%).
We also analyzed the correlations between DLE indicators and VCAM-1 and CXCR4 expression, as well as between VCAM-1 and CXCR4 expression. The results are presented in Figure 10 and Tables 12, 13, and 14.
Analysis revealed that the intensity of delayed phosphorescence (indicator 2) positively correlated with both VCAM-1 and CXCR4 expression in LN follicles. We did not identify any other correlations between CXCR4 expression in ALNs and DLE indicators. However, VCAM-1 expression in the follicles was negatively correlated with SOSDF (indicators 1 and 3) and positively correlated with the duration (indicator 5) of delayed phosphorescence. Furthermore, positive correlations were detected between indicator 2 and VCAM-1 expression in the LN cortex and medulla and between indicator 5 and VCAM-1 expression in the LN medulla.
With respect to the correlation between VCAM-1 and CXCR4 expression in the ALNs, the most significant correlations were between marker expression in LN follicles. Furthermore, significant correlations were detected between marker expression in LN sinuses and the medulla, as well as between VCAM-1 expression in the medulla and CXCR4 expression in LN follicles and the cortex. We studied the concordance of the CXCR4 and VCAM-1 expression values in the sinuses, follicles, medulla, and cortex and reported that the PPA values were 32.5%, 50%, 35.5%, and 44.8%; the NPA values were 79.3%, 83.3%, 100%, and 57.1%; and the ORA values were 51.4%, 66.7%, 44.4%, and 44.4%, respectively. The Cohen’s kappa indices for VCAM-1 and CXCR4 expression in the LN sinuses, LN follicles, LN cortex, and medulla were 0.105 ± 0.09 (95%CI: -0.077 to 0.287), 0.333 ± 0.10 (95%CI: 0.128-0.539), -0.075 ± 0.09 (95%CI: -0.252 to 0.103), and 0.132 ± 0.05 (95%CI: 0.043-0.222), respectively. These results indicate weak agreement between VCAM-1 and CXCR4 expression in LN follicles.
DISCUSSION
Photoluminescence methods are widely used in biology and medicine to study the metabolism of various cells and tissues, the structure of molecules, and cellular responses to various stimuli, as well as in the diagnosis of various diseases[20-23], including malignant neoplasms[24-27].
Photoluminescence is the process by which an atom or molecule emits light after it absorbs electromagnetic radiation, including ultraviolet, visible, or infrared light. There are three types of photoluminescence: Fluorescence, phosphorescence, and delayed fluorescence[28,29]. Currently, fluorescence-based diagnostic methods are predominantly used to study tumor cell metabolism and its changes under the influence of antitumor therapy. For example, fluorescence lifetime imaging (FLIM) is used to track biological molecules such as nicotinamide adenine dinucleotide phosphate, flavin adenine dinucleotide (FAD), tryptophan, and other molecules[30-32]. A study by Plekhanov et al[31] revealed differences in the kinetics of NAD(P)H fluorescence decay between metastatic BC cells and the primary tumor, as well as between metastatic cells and LN tissue, in a 4T1 mouse model. The authors reported that compared with lymphoid tissue cells, tumor cells have a greater contribution of free NAD(P)H (a1), i.e., the form associated with glycolysis, to fluorescence decay and, consequently, a shorter average lifetime τm (P < 0.001).
In an in vitro experiment, Benavides demonstrated the feasibility of using FLIM assessment of NADH and FAD autofluorescence for rapid analysis of BC tissue biopsies. The authors reported shorter lifetimes of NADH for cancer tissues than for noncancerous tissues and for metastatic BC cells than for nonmetastatic breast BC cells[33].
A study by Alam et al[30] revealed that in vitro treatment of prostate cancer cells with doxorubicin decreased the proportion of free NAD(P)H (a1) and increased the fluorescence lifetime and the proportion of NAD(P)H (a2) bound to the enzyme (a2%), which led to the induction of apoptosis in tumor cells. Similar results were obtained when metabolic changes in triple-negative BC (TNBC) cells in response to immunotherapy were studied. The authors believe that this method can be successfully applied to monitor and predict tumor response to drug therapy[34].
In this study, we examined DLE indicators in ALNs and their correlations with VCAM-1 and CXCR4 expression in the T and B zones of ALNs in patients with stage T1-T2 BC. Unlike the FLIM method, which evaluates changes in autofluorescence in a pool of biological molecules responsible for cellular respiration, assessing the dynamics of DLE indicators determines the characteristics of tissue molecular oxygen consumption. Previous studies have shown that the presence of malignant cells in the mammary tissues of experimental animals and patients with BC is characterized by a decrease in the SOSDF intensity and an increase in the intensity and duration of phosphorescence, indicating more active molar oxygen consumption by tumor tissues than by nontumor tissues[11,12].
To evaluate DLE indicators and VCAM-1 and CXCR4 expression in ALNs, we divided the studied LNs into three groups, namely, normal LNs, LNs with metastases, and reactive LNs, as we hypothesized that metabolic processes in these LN groups may differ significantly. We found that the SOSDF indices (indicators 1, 3, and 4) in LNs with metastases were significantly lower than those in normal and reactive ALNs, whereas the indices of delayed phosphorescence (indicators 2 and 5) were significantly greater in LNs with metastases. The DLE indicators did not differ significantly between normal and reactive LNs.
Thus, regardless of whether breast tissue or ALNs were studied, the results obtained indicate that compared with noncancerous tissue, cancerous tissue consumes molecular oxygen more actively. Considering that in the experiments, a decrease in the intensity of SOSDF indicators was observed only in oxygen-containing environments and that when air was replaced with nitrogen in the studied samples, no differences in the dynamics of DLE indicators were observed[35,36], it can be assumed that differences in the dynamics of DLE indicators are not determined by the value of the partial pressure of oxygen or the content of molecular oxygen in the tissues but depend on other factors, for example, the rate of oxygen diffusion in different tissues[37]. Thus, some studies have shown that tumor tissue has high interstitial pressure and a high concentration of collagen, which can impede the diffusion of molecules, including oxygen, from the vascular bed into tumor tissue[38]. Furthermore, oxygen diffusion in tissues may be related to the density of the tissues being examined[39,40]. It can be hypothesized that denser metastatic tissue in ALNs is associated with lower oxygen diffusion, which may influence the SOSDF values.
Another important factor that may influence the dynamics of SOSDF values is the rate of molecular oxygen consumption in tissues. A number of experimental studies have shown that different tissues have different rates of oxygen consumption[41]. High oxygen consumption may be associated with high cell density[39,42,43], as well as high adaptation to hypoxia, for example, in fetal and malignant cells[43]. In a study by Anbaei et al[44], the rate of oxygen consumption in native lymphoid tissue was higher in the T-cell region than in the B-cell and LN cortex regions. An in vitro experiment revealed that in the germinal centers (GC) of LNs, a normal pO₂ level is required for B-cell differentiation into functional lymphocytes, whereas CD27++ memory B cells, on the contrary, are generated under hypoxic conditions[45]. Given that oxygen plays a key role in respiration, metabolism, and energy production, the mechanisms underlying differences in oxygen consumption rates between tumor and nontumor tissues are undoubtedly of considerable interest.
Notably, studies evaluating the morphological features and expression of various markers in regional LNs in patients with malignant neoplasms are very rare. The few studies that have been conducted have revealed characteristic changes in tumor-draining LNs that occur before tumor cells reach them. For example, in syngeneic C57BL/6 mice implanted with B16-F10 melanoma cells, a significant increase in the number of lymphatic sinuses was observed in the tumor-draining LNs. Because these changes were observed before the melanoma cells reached them, the authors suggested that the primary tumors caused these changes remotely[46]. Expansion and an increase in the number of lymphatic sinuses in tumor-draining LNs, preceding metastasis, have also been noted by other researchers[47,48]. It is believed that in this way, the primary tumor prepares the tumor for metastasis.
In a mouse model, after the introduction of Lewis lung carcinoma cells into the lung, increases in the number of dendritic cells expressing cyclooxygenase-2, the expression of stromal cell-derived factor-1, the accumulation of regulatory T cells (Tregs), and the number of tumor cells expressing CXCR4 were observed in the subcapsular regions of the draining LNs. The authors believe that these changes indicate the involvement of these factors in the formation of premetastatic niches in the draining LNs[49]. In a study by Grigoriadis et al[50], tumor-draining LNs were assessed on the basis of the number, size, and location of GCs. The authors reported that in LNs with metastases, GCs were predominantly located at the periphery (52.6%) or in the center of the LNs (21.6%). However, no significant differences were found in the number or location of large GCs in LNs with and without metastases. The number and size of GCs in LNs with and without metastases were positively associated with the level of immune infiltration of the primary tumor (P < 0.001). The inclusion of the number, size and location of GCs in the prognostic model for assessing the risk of distant metastasis of BC, in combination with clinical and morphological characteristics and immune infiltration of the primary tumor, made it possible to improve the accuracy of predicting 5-year survival without distant metastases from 50% to 64% for all cases of BC and from 58% to 74% for TNBC[50].
A study by Seidl et al[51] revealed differences in tumor-draining LNs in patients with BC depending on the clinicopathological characteristics and molecular biological subtype of the tumor. The authors reported that with increasing T stage, the follicle density and the number of GCs increase, and they become more rounded, while the size of the mantle zones decreases. Follicle density was greater in LNs with hormone receptor-positive (HR-positive) HER2-positive and TNBC, whereas HR-positive BC showed more pronounced macrophage infiltration in the LN cortex. In LNs with metastases and nonsentinel LNs, lymphoid follicles have a more rounded shape[51]. In LNs with metastases, an increase in the number and size of GCs was observed, while the subcortical T zone decreased in size, but the number of T-regulatory lymphocytes (T-tregs) increased. Furthermore, in tumor-affected LNs, increased collagen production by fibroblastic reticular cells and recruited cancer-associated fibroblasts was observed. In veins with a thick endothelium, an increase in the lumen diameter and thinning of the endothelial layer were observed[52].
We investigated VCAM-1 and CXCR4 expression in the ALNs of patients with BC because these markers are associated with tumor progression factors[53]. VCAM-1 is a 110 kDa glycoprotein that belongs to the immunoglobulin superfamily of adhesion molecules. VCAM-1 is constitutively expressed on macrophages, dendritic cells and epithelial cells, as well as on the surface of stimulated endothelial cells, and can promote angiogenesis, survival and metastasis in cancer cells[54-56]. VCAM-1 is highly expressed in malignant tissues and cell lines and is associated with disease progression[17]. VCAM-1 binding to its ligand α4β1 integrin in the corresponding organs can mediate BC metastasis to the lungs, bones and brain[55,57]. VCAM-1 binding to α4β1 integrin on the lymphatic endothelium of LNs leads to tumor cell adhesion to lymphatic vessels and BC metastasis to the LNs[58]. Some studies have shown that VCAM-1 expression by tumor cells may be involved in the creation of a premetastatic niche. For example, a study by Narasimhan et al[59] revealed that treatment of TNBC stem cells with tumor necrosis factor-α increases VCAM-1 expression in the liver, which leads to the formation of a premetastatic niche in the liver of tumor-bearing mice. In an experiment, extracellular vesicles derived from melanoma cells were transported to draining LNs, and this process partially depended on VCAM-1 expression by lymphatic vessels in the LNs[60]. In patients with BC, serum VCAM-1 levels correlated with tumor microvessel density and were higher in patients who developed early recurrence than in patients without recurrence (P = 0.01)[61].
CXCR4 is an integral membrane protein that specifically binds to C-X-C motif chemokine ligand 12 (CXCL12). CXCR4 is expressed by lymphocytes, endothelial cells, hematopoietic stem cells, fibroblasts, and tumor cells[62]. According to a meta-analysis, the overall prevalence of CXCR4 expression in primary BC is 46% (from 8% to 100% according to different studies). The prevalence of CXCR4 increased with increasing tumor grade (26% at G1, 32% at G2, and 44% at G3; P < 0.001). However, the highest level of marker expression occurred at stage T1 BC[63]. In a study by Rusetska et al[64], CXCR4 expression in the LNs of patients with vulvar squamous cell carcinoma was detected both in tumor cells (in 98% of cases) and in lymphocytes in LNs with metastases (50%) and without metastases (50%).
Activation of marker expression occurs under the influence of hypoxia, vascular endothelial growth factor, nuclear factor kappa B, estrogens, transforming growth factor β1, β-catenin, and interferon γ[63,65,66]. The interaction of CXCR4 with CXCL12 activates various pro-oncogenic signaling pathways, resulting in the stimulation of tumor cell chemotaxis and proliferation and the enhancement of tumor cell invasive and metastatic properties[66-69]. CXCR4 is involved in the HER2 activation, angiogenesis, proliferation and metastasis of tumor cells and promotes immune evasion and drug resistance through epithelial-mesenchymal transition, cancer cell stemness and interactions with the tumor microenvironment[65,70-73]. Furthermore, the CXCL12/CXCR4 signaling pathway is involved in the creation of a premetastatic niche in draining LNs[74].
Some studies have shown that VCAM-1 and CXCR4 may be involved in the metabolic reprogramming of cells toward the glycolytic pathway[15-17,73]. For example, the paracrine induction of VCAM-1 increased lactate production in pancreatic cancer cells, indicating their reprogramming toward the glycolytic pathway[17]. Lactate production induced by VCAM-1 expression activated macrophages, leading to a phenotype similar to that of tumor-associated macrophages (TAMs). TAMs are known to undergo metabolic reorganization, which ultimately promotes the invasion and metastasis of malignant neoplasms[75], as well as immunosuppression[76]. CXCL12 signaling through CXCR4 increases the amount of intermediate metabolites involved in glycolysis and the pentose phosphate pathway[15]. The CXCL12/CXCR4 axis not only promotes metabolic reorganization but also increases the migratory properties of tumor cells[16]. Suppression of CXCR4 expression in osteosarcoma cells overcame cell resistance to doxorubicin by changing glycolytic activity and increasing the sensitivity of tumor cells to apoptosis[73].
A study of VCAM-1 and CXCR4 expression in ALNs revealed that moderate and high expression of these markers in LN follicles was significantly more common in metastatic LNs than in nonmetastatic LNs (P = 0.0082 and P = 0.0270, respectively). Furthermore, we found that the expression of CXCR4 and VCAM-1 in LN follicles was positively correlated with each other and the duration of phosphorescence (indicator 5), whereas the expression of VCAM-1 in LN follicles was negatively correlated with the expression of SOSDF indicators (indicator 3 and indicator 4). This finding is very interesting and important and indicates that metabolic changes similar to those characteristic of malignant neoplasms are observed in LN follicles and that this process is associated with CXCR4 and VCAM-1 expression. Recent research suggests that metabolic reprogramming of cells toward aerobic glycolysis (the Warburg effect) is critical not only for malignant growth but also for many physiological and pathological processes, including the regulation of innate and adaptive immunity. The key role of aerobic glycolysis is that lactate, its primary product, is also the primary source of carbon for the Krebs cycle and, therefore, energy[77,78]. In addition, lactate is directly involved in posttranslational modifications of proteins and epigenetic regulation[79], thereby participating in various physiological processes and diseases, including autoimmune disorders[80], cardiovascular diseases[81], infections[81] and cancer[82,83]. In malignant tumors, high lactate production disrupts mitochondrial function and increases the expression of glycolytic enzymes and monocarboxylate transporters. As a highly active signaling molecule, lactate is involved in the activation of angiogenesis, tumor cell migration and metastasis, and immune surveillance evasion[82]. The correlations observed in this study may be related to metabolic reprogramming of tumor and immune cells, which promoted the activation of CXCR4 and VCAM-1 expression.
The results of many studies indicate that the characteristics of the primary tumor influence the expression patterns of markers in draining LNs[50,51,84]. Primary tumors can actively induce lymphangiogenesis, promote the formation of premetastatic niches, and metastasize to secondary organs, including LNs[85-87]. The results of these studies suggest that the CXCL12/CXCR4 axis may play an important role in their development[49,74,86]. Tumor-target organ interactions are mediated by exosomes, extracellular vesicles, chemokines, cytokines, growth factors, long noncoding RNAs, microRNAs and other factors released or secreted by tumor cells[85,86,88,89].
On the basis of the above findings, we analyzed DLE indicators and VCAM-1 and CXCR4 expression levels according to BC characteristics. We found that SOSDF indicators were negatively correlated with tumor progression factors such as stage N, tumor grade, and LVI, whereas indicators 2 and 5 were positively correlated with stage N and LVI. The lowest SOSDF indicator values were observed for stages N2–N3, tumor grade 3 (G3), LVI, and a Ki67 index ≥ 40%.
With respect to VCAM-1 and CXCR4 expression, the expression of both markers correlated with different factors of BC progression. VCAM-1 expression in ALNs was most significantly (P < 0.001) positively correlated with tumor grade, HER2 status, and the Ki67 index and negatively correlated with ER status, whereas CXCR4 expression in LN follicles and the medulla was positively correlated with N stage, LVI, and HER2 status, and CXCR4 expression in the LN cortex was positively correlated with tumor grade and the Ki67 index. Expressed VCAM-1 expression in LN sinuses, LN follicles, the LN cortex, and the LN medulla was associated with tumor grade 3, HER2-positive BC, and a Ki67 index ≥ 40%. CXCR4 expression in LN follicles was associated with the presence of metastases in ALNs and the presence of LVI. Of interest are the negative correlations between CXCT4 expression in LN sinuses and T stage and the positive correlation between CXCR4 expression in LN follicles and LN medulla and PR status. This may be due to the different roles that CXCR4 expression plays in early and advanced cancers. In Adams’ study, the highest marker expression level was also observed in stage T1 BC[63].
CONCLUSION
Thus, the results indicate that metastatic LNs exhibit decreased SOSDF values and increased values associated with both the intensity and duration of phosphorescence, indicating greater oxygen consumption by tumor cells. Changes in tumor cell metabolism are associated with increased CXCR4 and VCAM-1 expression in ALNs. Given that increased marker expression is observed in both metastatic and nonmetastatic LNs in patients with LN metastases, these results support the findings of other researchers that CXCR4 and VCAM-1 may be involved in the formation of a premetastatic niche in tumor-draining LNs. The correlations between DLE, VCAM-1, and CXCR4 expression in ALNs support the hypothesis that primary tumor characteristics may influence marker expression patterns in regional LNs. However, this study has several significant limitations. First, this is an observational study and is therefore susceptible to confounding factors and potential bias. Second, limitations include the limited number of patients with aggressive BC subtypes, the predominance of stage I-II disease, and, consequently, the small number of metastatic LNs examined. Furthermore, this study reflects the VCAM-1 and CXCR4 expression status of only tumor cells in ALNs with metastases, while data on the expression status of VCAM-1 and CXCR4 in primary breast tumors are lacking, which is also a major limitation. Another limitation is that, for technical reasons, we studied DLE indicators and marker expression in level 1 ALNs, whereas for diagnostic purposes, it is important to study these markers in sentinel LNs. In addition, to improve the objectivity of marker expression assessment, standardization of the assessment method and clinical and analytical validation, including the evaluation of reagents, equipment, test systems, and other influencing factors, are necessary. We believe that further studies of DLE indicators and VCAM-1 and CXCR4 expression in sentinel LNs and primary tumors, as well as their correlation with the clinicopathological characteristics and molecular biological characteristics of patients with BC, may be highly important.
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Corresponding Author's Membership in Professional Societies: Petrovsky National Research Centre of Surgery, Petrovsky National Research Centre of Surgery.
Specialty type: Medicine, research and experimental
Country of origin: Russia
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P-Reviewer: Budaya TN, MD, Postdoc, Indonesia; Mondal K, Chief, Consultant, MD, India S-Editor: Qu XL L-Editor: A P-Editor: Yang YQ
