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Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer

BMC Cancer volume 24, Article number: 1132 (2024) Cite this article

Abstract

Objective

To investigate the impact of vasculogenic mimicry (VM) and postoperative adjuvant therapy on the prognosis and survival of patients with esophageal squamous cell carcinoma (ESCC), as well as to assess whether VM affects the clinical benefit of postoperative adjuvant therapy.

Methods

This single-center retrospective analysis included patients who underwent radical surgery for ESCC, which was documented in the medical record system. The presence or absence of VM in surgical specimens was determined using double staining with PAS/CD31. Stratification was applied based on adjuvant therapy and VM status. Survival curves and COX modeling were used to analyze the impact of the presence or absence of VM on the benefit of adjuvant therapy and the survival prognosis of patients.

Results

VM-positive patients were more prone to postoperative recurrence and metastasis. VM was identified as an independent risk factor for progression-free survival (PFS) (p < 0.001, 95% CI:1.809–3.852) and overall survival (OS) (p < 0.001, 95% CI:1.603–2.786) in postoperative ESCC. Postoperative adjuvant therapy significantly prolonged PFS (p = 0.008) and OS time (p < 0.001) in patients with stage II and III ESCC, with concurrent chemoradiotherapy being the most effective. However, the presence of VM significantly reduced the benefits of postoperative adjuvant therapy (p < 0.001).

Conclusion

VM negatively impacts the prognosis of postoperative ESCC patients and reduces the efficacy of postoperative adjuvant therapy.

Peer Review reports

Background

Esophageal squamous cell carcinoma (ESCC) is a prevalent upper gastrointestinal malignancy found in many economically underdeveloped countries and regions, including China. Except for cervical esophageal cancer, surgical resection is considered the standard treatment [1]. Despite the advancements in postoperative adjuvant therapy, which complements surgical resection and enhances prognosis beyond the T1N0 stage, a considerable proportion of patients still experience regional lymph node recurrence and distant organ metastasis, which indicates that the current adjuvant treatment strategy may overlook undefined prognostic risk factors. Therefore, further clarification of such factors is of crucial importance to refine adjuvant treatment strategies and postoperative survival in patients with ESCC.

Vascular mimicry (VM) represents a new model of blood supply within tumors, wherein highly invasive tumor cells remodel into vascular-like channels to self-nourish [2]. VM typically thrives in hypoxic regions intimately tied to tumor cell heterogeneity and microenvironment remodeling [3]. VM promotes the exchange of substances between the local microenvironment, including tumor cells, and the external milieu, fostering systemic symptoms and distant metastasis of the tumor. While some studies [4] have detected an adverse impact of VM on postoperative survival of esophageal cancer, none have scrutinized the relationship between VM and postoperative adjuvant therapy or delineated its intrinsic link with clinical recurrence and progression manifestations post-adjuvant therapy, which is why the influence of adjuvant therapy on the postoperative survival benefit of VM-positive patients remains unclear.

At present, prophylactic radiotherapy with a local tumor bed plus regional draining lymph nodes and systemic therapy are standard postoperative adjuvant treatment approaches for esophageal cancer [5, 6]. Recurrence progression under these conditions, characterized by lymph nodes and metastasis to distant organs and tissues, is closely related to the early escape of tumor cells from the primary lesion and adjuvant therapy resistance. Further deterioration of the tumor cell phenotype (stem cell-like differentiation, epithelial-mesenchymal transition, and epithelial endothelial-like transition) promotes the formation of VM, often closely linked with the acquisition of adjuvant therapy resistance at the primary site. At the same time, the formation of primary lesion hemangiomas provides a direct pathway for metastasis of tumor cells [7]. Thus, intervening in VM could potentially mitigate postoperative recurrence and progression risk in ESCC patients with such pathologies.

The mechanism of VM formation is complex, involving abnormal activation of multiple signaling pathways and signaling attenuation. Similarly, postoperative adjuvant therapy mechanisms are complex and are all directed toward improving prognosis, quality of life, and prolonging survival time. Currently, there is a dearth of research on the relationship between VM and postoperative adjuvant therapy. Thus, the present study focused on elucidating whether VM affects the prognosis of postoperative ESCC and the efficacy of postoperative adjuvant therapy and if current postoperative adjuvant therapy suppresses VM, aiming to establish a foundation for developing a comprehensive therapeutic strategy for patients with VM-positive ESCC.

Methods

Patient information and tissue sample sources

Patients with esophageal cancer who underwent surgical treatment at the Second People’s Hospital of Taizhou City between 2010 and 2015 were recruited in the study. Inclusion criteria were the following: (1) patients undergoing surgical treatment at the Second People’s Hospital of Taizhou City with the same surgical style and operator; (2) postoperative pathological confirmation of squamous carcinoma; (3) availability of comprehensive patient information, including preoperative, hospitalization, follow-up adjuvant treatment, and survival of all patients at the end of follow-up. Exclusion criteria were: (1) patients diagnosed with pathologic types other than squamous carcinoma; (2) patients with revised diagnosis; (3) patients receiving neoadjuvant therapy prior to surgery; (4) patients experiencing severe treatment complications interrupting or resulting in postoperative death.

The patient’s prognosis was recorded through outpatient review and telephone follow-up. The following variables were collected: gender, age, lesion site, grade of differentiation, cancer embolism, T-stage, N-stage, clinical stage, vascular mimicry, lesion length, adjunctive treatment, OS time, and PFS time. OS was defined as the duration from surgery to death or the last follow-up date; PFS was defined as the period from the day after surgery to the date of disease recurrence, metastasis, or last follow-up.

This single-center retrospective study adhered to the Declaration of Helsinki and relevant Chinese laws and received approval from the Ethics Committee (Project Ethics No. TZEYLL20170401).

CD31/PAS double staining and analysis of VM

CD31-PAS double staining was used to identify VMs and endothelial-dependent vessels (EDVs). Paraffin-embedded tissues were serially sectioned at 4 μm, followed by dewaxing and hydration. The CD31/PAS immunohistochemical staining (the primary and secondary antibodies were purchased from Shanghai Long Island Antibody Diagnostic Reagent Co.) was done following the previously reported procedures [8, 9]. Briefly, after antigen repair, the sections were incubated overnight at 4 °C with primary antibody (CD31 antibody reagent, JC/70A/rabbit poly antibody, product no. 0114, 1:200), after which they were incubated with biotinylated secondary antibody for CD31 staining, and then stained with PAS staining (Beijing Ruigen Bio-Reagent Co.) [10]. Staining results were observed under a light microscope (Olympus).

Hematoxylin-Eosin staining (HE)

HE staining was used to characterize cancer tissue and its pathological properties. Paraffin sections underwent sequential staining with hematoxylin for 5 min and eosin for 3 min after dewaxing, dehydrating, and repairing. Stained sections were dehydrated with anhydrous ethanol, permeabilized with xylene, and finally sealed with neutral resin. Observations were made using an optical microscope (Olympus).

Data analysis

SPSS Statistics 25.0 was used for all statistical analyses (IBM, Armonk, NY, USA). Categorical variables were numerically expressed and comparatively analyzed using the chi-square test, while the Mann-Whitney U test was used to analyze grade variables. Grouping was done using binary logistic, and survival analysis and comparison of survival time were done using the Kaplan-Meier and Log-rank tests. The relationship between each factor and postoperative recurrence metastasis was analyzed using the Cox regression modeling. A two-sided P < 0.05 represented statistical significance.

Results

Demographic and clinical characteristics of patients

Among a total of 301 patients who underwent surgery for esophageal cancer and were initially included in this study, 12 patients with esophageal adenocarcinoma and 1 with spindle cell carcinoma were excluded, resulting in 288 patients with ESCC who met the study criteria. Among them, 230 (79.9%) were men and 58 (20.1%) were women; the oldest was 82 years old, the youngest was 39 years old, with a median age of 67. There were 160 patients (55.6%) who were 67 years old or younger and 128 (44.4%) older than 67 years old.

Regarding histological differentiation, 37 patients (12.8%) had high-differentiated squamous carcinoma, 173 had (60.1%) moderately-differentiated carcinoma, and 78 had (27.1%) poorly-differentiated carcinoma (27.1%). There were 75 patients (26.0%) with stage I tumor, 94 patients (32.6%) with stage II tumor, and 119 patients (41.3%) with stage III tumor. Also, 182 patients (63.2%) were with a lesion length of < 5 cm, and 106 (36.8%) with a lesion length of > 5 cm (Table 1).

Table 1 Demographic and clinical characteristics of the patients
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Morphologic structure and detection rate of VM in ESCC

Pathological specimens were analyzed using HE staining and a CD31/PAS staining comparison. Endothelial dependent vessel (EDV), mosaic vessel (MV), and vasculogenic mimicry (VM) were found, respectively. CD31-negative/PAS-positive vascular structures were classified as VM, CD31-positive/PAS-negative vascular structures as EDV, and CD31/PAS double-positive vascular structures as MV. A total of 94 cases (32.6%, 94/288) of ESCC tissues exhibited VM structures, characterized by tubular structures away from the EDV region, PAS-positive/CD31-negative, with visible circulating erythrocytes within (Fig. 1B-E). Statistically, VM-positive patients had a lower differentiation grade (p = 0.044), a higher probability of presenting VTT (p < 0.001), and a late N stage and clinical stage (p < 0.001, p < 0.001), while no significant difference was observed in gender, age, lesion site, and T stage (all p > 0.05). The presence or absence of VM structures showed near variability in the length of primary lesions (p = 0.054), with no significant difference based on Fisher’s exact examination (p = 0.068, Table 1).

Fig. 1
figure 1

HE staining and PAS/CD31 double staining of pathological specimens to identify VM. (A) HE staining of ESCC tissue (scale from left to right 5 mm, 500 μm, 100 μm). (B) CD31/PAS double staining of ESCC tissue. CD31 is shown in brown; PAS is shown in violet red (scale 2000 μm). Partial magnification (scale 50 μm). EDV (CD31+/PAS-) is indicated in the green area, MV (CD31+/PAS-) in the yellow area, and VM (CD31-/PAS+) in the red area (scale 5 μm). (C) The green arrow points to EDV (scale 5 μm). (D) The yellow arrow points to MV (scale 5 μm). (E) The red arrow points to VM (scale 5 μm)

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Effect of VM on recurrent metastasis and survival after ESCC surgery

The median PFS in VM-positive cases was 360 days (319.14-400.76), which was significantly shorter than the 907 days (766.10-1047.40) observed in VM-negative cases (Log-rank test, p < 0.001, Fig. 2a). The median OS was 599 days (456.48-741.52) in VM-positive cases, which was significantly shorter than 1106 days (924.18-1287.82) in VM-negative cases (Log-rank test, p < 0.001, Fig. 2b). According to COX model analysis, VM was an independent risk factor affecting PFS (HR: 2.387, 95% CI: 1.809–3.152) and OS (HR: 0.531 and 95% CI: 0.384–0.734) after surgery (Tables 2 and 3).

Among the 288 ESCC patients, 213 (74%, 213/288) experienced recurrent progression, with 85 (40%, 85/213) exhibiting local recurrence and 128 (60%, 128/213, Fig. 2c) distant metastases. Common sites of metastasis included the lungs in 74 patients (34.7%, 74/213), the liver in 41 patients (18.8%, 41/213), lymph nodes outside the local drainage area in 22 patients (10.3%, 22/213), and bone metastases in 30 patients (14.1%, 30/213, Fig. 2d). In the VM group, 85 patients (90.4%, 85/94) developed recurrent metastases compared to 128 patients (66%, 128/194) in the no-VM group, suggesting a higher likelihood of recurrent metastases in the VM group, predominantly in distant metastases.

Fig. 2
figure 2

Survival curves, progression, and site frequency distribution plots for VM(+) and VM(-) patients. (a) PFS survival curve. (b) OS survival curve; PFS and OS in the VM(+) group were shorter than those in the VM(-) group, and the difference between the two groups was statistically significant (P < 0.001). (c) Frequency table of recurrence rates in patients with VM(+) and VM(-), with a recurrence rate of 90.4% in the positive group and 66% in the negative group. (d) The distribution of recurrence sites in VM(+) and VM(-).p < 0.05 was considered a statistically significant difference

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Table 2 Univariate and multivariate analyses of progression-free survival among patients with ESCC
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Table 3 Univariate and multivariate analyses of overall survival among patients with ESCC
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Impact of VM on postoperative adjuvant therapy for ESCC

Among the 288 patients, 213 (74.0%) had stage II-III ESCC, with 155 (72.8%) receiving postoperative adjuvant therapy (Fig. 3a). The median PFS was about 561 days (485.64-635.36) in the postoperative adjuvant therapy group and about 405 days (317.73-492.07) in the no postoperative adjuvant therapy group, showing a significant difference between the two groups (p = 0.0084, Fig. 3b, left). The median OS was about 898 days (753.75-1042.26) in the postoperative adjuvant therapy group and about 589 days (510.63-667.37) in the no postoperative adjuvant therapy group (Log-rank test, p < 0.001, Fig. 3b, right). Stage II and III postoperative patients receiving adjuvant therapy exhibited longer PFS and OS compared to those who did not receive adjuvant therapy.

The median PFS in the postoperative adjuvant therapy group receiving only chemotherapy was 401 days (307.38-494.62), 561 days (488.52-633.49) in the group receiving radiotherapy alone, and 799 days (646.78-951.22) in the simultaneous chemoradiotherapy group, showing statistical differences among the three groups (Log-rank test, p = 0.001, Fig. 3c, left); the synchronous radiotherapy yielded the longest PFS among the three adjuvant therapies, which was also reflected in OS (Log-rank test, p = 0.004, Fig. 3c, right). Cox model analysis showed that postoperative adjuvant therapy reduced the risk of postoperative recurrent progression by 46.2% in stage II and III patients (HR: 0.649 95% CI: 0.469–0.898, Fig. 3d).

The median PFS for patients with VM in stage II and III who did not receive postoperative adjuvant therapy was approximately 273 days (186.10-359.90). The median PFS for those receiving radiotherapy alone was 330 days (0-739.05), 341 days (225.09-456.91) for those receiving chemotherapy, and 580 days (369.98-790.02) for those receiving concurrent radiotherapy and chemotherapy, with no significant difference among the four groups (Log-rank, p = 0.056, Fig. 4c); the median OS was 343 days (182.12-503.88), 506 days (465.10-546.91), 494 days (331.73-656.27), and 860 days (581.27-1138.73), respectively, with no significant difference among the four groups (Log-rank, p = 0.152, Fig. 4d). These results showed no significant prolongation of PFS and OS by adjuvant therapy in VM-positive patients and no significant differences between adjuvant treatments.

Among patients without VM in stage II and III, the median PFS for patients without postoperative adjuvant therapy was 448 days (387.53-508.47), 753 days (394.37-1110.65) for radiotherapy alone, 607 days (204.59-1009.41) for chemotherapy alone, and 1192 days (796.28-1587.72) for simultaneous radiotherapy and chemotherapy, with a significant difference among the four groups (Log-rank, p < 0.001, Fig. 4g). The median OS was 662 days (474.02-849.97) for no adjuvant therapy, 980 days (793.64-1166.35) for radiotherapy alone, 811 days (417.12-1204.88) for chemotherapy alone, and 1446 days (1086.60-1805.40) for concurrent radiotherapy and chemotherapy, with a significant difference between the three groups (Log-rank, p < 0.001, Fig. 4h). The results showed that postoperative adjuvant therapy effectively prolonged PFS and OS and improved prognosis in stage II and III, with concurrent radiotherapy and chemotherapy being particularly effective.

Survival analyses of patients in the VM (+) and VM (-) groups in stage II and III showed that patients in the VM-negative group had a median survival and OS approximately two times longer than that of the VM group in the absence of adjuvant therapy. The three adjuvant treatment modalities presented a more favorable therapeutic effect in the group without VM than the group with VM, resulting in prolonged PFS and OS by more than one year. The analysis showed that VM reduced the clinical benefit of postoperative adjuvant therapy in patients with ESCC.

Fig. 3
figure 3

Stage II-III patients who received adjuvant therapy, survival curves, and univariate analyses related to PFS. (a) Frequency plot of the distribution of untreated and three adjuvant treatment modalities in stage II/III patients. (b) PFS (left) and OS (right) survival curve analysis with/without adjuvant treatment; PFS (p = 0.008) and OS (p < 0. 001) were significantly prolonged in the adjuvant treatment group. (c) PFS (left) and OS (right) survival curve analysis of the three adjuvant treatment modalities; the synchronous radiotherapy group had the longest survival. (d) COX-related unifactorial (left) and multifactorial (right) PFS analysis in stage II/III patients, with VM as a risk factor and treatment as a protective factor. p < 0.05 indicates statistical significance

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Fig. 4
figure 4

Univariate analyses and survival curves related to adjuvant therapy for the VM(+) and VM (-) groups. (a, b) Forest plot of the univariate analysis of PFS (a) and OS (b) for patients in the stage II/III VM(+) group, with no significant effect of treatment on PFS and only concurrent chemoradiation therapy on OS. (c, d) Analysis of PFS (c) and OS (d) curves for patients with stage II/III VM(+) without adjuvant therapy and patients with stage II/III VM (+) with adjuvant therapy showed no significant differences between the four groups (p > 0.05). (e, f) Forest plot of factors associated with PFS (e) and OS (f) in patients in the no-VM group. (g, h) Survival curves for PFS (g) and OS (h) were analyzed for patients in the VM (-) group without adjuvant therapy and with three adjuvant treatment modalities

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Discussion

In recent years, several previous studies have demonstrated the association between vascular mimicry and tumor invasion, recurrence, metastasis, and poor prognosis, making VM a potential target for antitumor therapy [11,12,13]. In this study, we found a VM incidence of 32.6% (94/288, Fig. 2c) in resectable ESCC and a postoperative recurrence progression rate of 90.4% (85/94, Fig. 2c) in patients with VM structures. In addition, our findings showed that VM compromised the effectiveness of postoperative adjuvant therapy, with conventional adjuvant therapy failing to significantly prolong disease-free survival or OS in VM-positive patients based on relevant survival analyses. These results indicate that the formation of VM in ESCC not only accelerates postoperative recurrence and metastasis but also contributes to the resistance of tumors to conventional treatment. Thus, further studies on the mechanisms underlying VM formation are needed to mitigate its adverse effects on adjuvant therapy by intervening in its formation, ultimately reducing the risk of postoperative recurrence and metastasis in ESCC.

Since Maniotins et al. discovered and named the phenomenon of vascular mimicry in melanoma in 1999, many studies have reported on its pivotal role in tumor invasion and metastasis, with research on the mechanism of VM gradually deepening. However, due to the complexity of the VM itself, the mechanism of the VM should be fully elucidated. As indicated by numerous studies, hypoxia has emerged as a central factor in the formation of VM [14, 15]. In this study, the areas where the three vascular morphologies (VM, MV, and EDV) were present in the surgical specimens of ESCC had some regional differences (Fig. 1B, right). VM tends to occur in areas away from the EDV, typically in a hypoxic area that is close to the center of the tumor. In order to obtain nutrients and oxygen for their growth, tumors form VM that do not depend on endothelial cells but have endothelial-like vascular structure and function, so VM is predominantly located in the center of the tumor. Endothelium-dependent blood vessels are found in oxygen-rich areas, mostly at the margins away from the center of the tumor, and mosaic blood vessels are found at the junction of these regions. As oxygen concentration decreases, the sequential distribution of EDV, MV, and VM occurs.

Conventional postoperative adjuvant therapies for ESCC include radiotherapy, chemotherapy, and concurrent chemoradiotherapy. In this study, we found that the order of efficacy of the three modalities was simultaneous chemoradiotherapy > radiotherapy > chemotherapy. However, none of these conventional adjuvant therapies were effective in VM-positive patients. Previous studies on postoperative adjuvant therapy for ESCC have shown its clinical value [5, 16], revealing that postoperative chemotherapy (POCT) [17] improves the survival rate of lymph node-positive and -negative patients, and postoperative radiotherapy (PORT) [18] reduces the risk of tumor recurrence and prolongs survival time [19]. While conventional adjuvant therapy can temporarily impede the growth of tumors with VM, it lacks significant inhibitory effects on metastasis and malignancy in the distant future. The stemness and differentiation of tumor stem cells can drive VM formation, endowing it with the ability to establish blood transport pipelines, thus providing a pathway for tumor escape [20, 21]. Most current anti-angiogenic treatments are based on the theory of VM to develop drugs that inhibit tumor angiogenesis by targeting endothelial growth factors, aiming to correct tumor vascular system disorders and sever the tumor-donor connection [22, 23]. However, existing anti-angiogenic treatments do not effectively target VM, as it represents another mode of tumor microcirculation angiogenesis, and their hypoxia-causing side effects may accelerate VM formation [14, 24,25,26,27]. It is of utmost urgency to update the strategy for the comprehensive treatment of ESCC. For doctors concerned about the poor results of postoperative adjuvant therapy in some patients, our study provides new clinical ideas to predict the growth potential and prognosis of tumors by detecting vascular mimicry. Secondly, therapeutic strategies based on vascular mimicry open new avenues for anti-tumor research and help develop new treatments and drugs. Our findings also provide the basis for developing personalized treatment protocols, allowing the use of the most appropriate VM-targeted therapies for specific individual conditions. Finally, it is essential in optimizing and improving patient prognosis and prognostic assessment.

The present study confirms that VM and postoperative adjuvant therapy are opposing factors in ESCC, highlighting a subtle relationship between these factors. Specifically, VM significantly reduces the efficacy of postoperative adjuvant therapy, while the inability of conventional adjuvant therapy to effectively suppress angiogenesis leads to a lack of clinical benefit in adjuvant therapy in angioma-positive patients, contradicting the original therapeutic intent and posing a significant challenge to clinicians and patients alike. Breaking the unilateral influence of VM on the effectiveness of postoperative adjuvant therapy for ESCC is essential to offer more comprehensive treatment options for ESCC patients. Therefore, in-depth studies into the relevant signaling pathways and key genes involved in VM formation and its mechanisms are warranted to provide a solid theoretical basis for subsequent drug development and the expansion of therapeutic modalities. Since this is a retrospective study, the sample size was limited, and there was bias in variables such as age and gender, which may affect the results to some extent. In the follow-up study, we plan to expand the sample size and conduct related studies in different hospitals and districts to test the accuracy of this study.

Conclusion

Our findings suggest that VM is an important risk factor affecting the prognosis of ESCC and that VM may exert its efficacy by interfering with postoperative adjuvant therapy, thereby accelerating disease progression. Therefore, we further pondered whether the clinical efficacy of adjuvant therapy could be improved by intervening in the formation of vascular stimulating hormones to improve the prognosis of ESCC.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

VM:

Vascular mimicry

ESCC:

Esophageal squamous cell carcinoma

PFS:

Progression-free survival

OS:

Overall survival

POCT:

Postoperative chemotherapy

PORT:

Postoperative radiotherapy

POCRT:

Postoperative chemoradiotherapy

EDV:

Endothelial dependent vessel

MV:

Mosaic vessel

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Acknowledgements

Not applicable.

Funding

This study was supported by the“333” High Level Talent Project of Jiangsu Province (no. BRA2020186), Major Project of Basic Science (Natural Science) Research in Higher Education Institutions in Jiangsu Province (no. 22KJA360009), Project of Yangzhou key discipline in oncology therapeutics (Project no. YZYXZDXK − 013), and the Key Project of Jiangsu Province Traditional Chinese Medicine Science and Technology Plan (no. ZD202330).

Author information

Author notes

  1. Jue Chen and Yu Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Affiliated Hospital of Yangzhou University, No. 368 Hanjiang Middle Road, Hanjiang District, 225001, Yangzhou, China

    Jue Chen

  2. Medical College of Yangzhou University, 225001, Yangzhou, China

    Jue Chen, Yu Wang, Mengke Wu, Keke Yu, Junchi Liu & Jiayu Chang

  3. The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the National Administration of Traditional Chinese Medicine, 225001, Yangzhou, China

    Jue Chen, Yu Wang, Mengke Wu & Keke Yu

Authors
  1. Jue Chen
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  2. Yu Wang
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  3. Mengke Wu
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  4. Keke Yu
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  5. Junchi Liu
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  6. Jiayu Chang
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Contributions

JC: Project administration, Conceptualization, Writing-review & editing, Funding acquisition, Supervision; YW: Writing-Original draft, Data curation; MKW: Formal analysis, Writing-embellishment; KKY: Formal analysis, Experiment, Data curation; JCL: Investigation, Documentation management; JYC: Validation, Documentation management. All authors reviewed the manuscript.

Corresponding author

Correspondence to Jue Chen.

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Ethics approval and consent to participate

The study was approved by the institutional review board of the second People’s Hospital of Taizhou City (No. TZEYLL20170401), and a waiver of informed consent was granted.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Chen, J., Wang, Y., Wu, M. et al. Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer. BMC Cancer 24, 1132 (2024). https://doi.org/10.1186/s12885-024-12903-5

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  • DOI: https://doi.org/10.1186/s12885-024-12903-5

Keywords

BMC Cancer

ISSN: 1471-2407

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