Compromised Endothelial Regeneration as a Potential Contributor to Long-Term Cardiovascular Complications in Childhood Cancer Survivors

Q: What are the key findings of this study?

Anthracycline-treated childhood cancer survivors had decreased endothelial progenitor cells (0.12%-2.6% of PBMCs) dominated by senescent p16+ cells (73%-95%) up to 1 year post-treatment.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Childhood leukemia (n=35) or lymphoma (n=13) (n=48). Intervention: Anthracycline chemotherapy vs. Age-matched healthy controls and pre-treatment baseline. Primary outcome: Longitudinal circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), and EPC fate (p16+ senescence and Annexin V+ apoptosis).

Q: What does this research mean for the field?

Childhood cancer survivors treated with anthracyclines experience prolonged impairment of endothelial repair characterized by depleted circulating endothelial progenitor cells that are predominantly senescent up to one year post-treatment. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Kasturi Markandran; Tricia Jingwen Ng; Elena Tan; Czaryna Kaye Mendoza Clemente; Rina Miao Qin Wang; Yee Phong Lim; Karan Attal; Kristine Nicole Mendoza Clemente; Hannah Su-Ann Wee; Hammresh S; Christine Cheung; Sik Yin Roger Foo; Ching Kit Chen

doi:10.3390/cells15212040

November 9, 2026CellsOpen Access

Compromised Endothelial Regeneration as a Potential Contributor to Long-Term Cardiovascular Complications in Childhood Cancer Survivors

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Key result

Anthracycline therapy linked to reduced endothelial progenitor cells dominated by up to ~95% senescent cells.

n=48

Why the study?

Anthracyclines predispose childhood cancer patients to cardiotoxicity and long-term cardiovascular risk, and while endothelial injury and impaired repair contribute to this process, pediatric data remain limited.

Does anthracycline chemotherapy impair endothelial injury and repair biomarkers (CECs and EPCs) and alter EPC cell fate up to 1 year post-treatment in children with leukemia or lymphoma?

Key Points

To longitudinally assess endothelial damage and vascular repair capacity in pediatric cancer patients receiving anthracycline chemotherapy by quantifying circulating endothelial cells and progenitor cells.
Single-centre retrospective cohort of pediatric patients (<18 years) diagnosed with leukemia (n=35) or lymphoma (n=13) evaluated across four timepoints: pre-treatment, ~1-month post-treatment, 3 months post-treatment, and 1 year post-treatment.
Flow cytometry of peripheral blood mononuclear cells was performed to quantify circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs), alongside EPC fate tracking using p16 (senescence) and Annexin V (apoptosis).
Left ventricular ejection fraction and cardiac biomarkers, including high-sensitivity troponin T (hsTnT) and NT-proBNP, were assessed longitudinally.
CECs peaked at pre-treatment (approximately 4-fold higher than healthy controls in leukemia and 5.5-fold higher in lymphoma) and subsequently declined post-treatment toward control levels, remaining only marginally elevated during remission.
Circulating EPCs significantly decreased below healthy control levels at the end of treatment, 3 months, and 1 year post-treatment in both leukemia and lymphoma cohorts.
Senescent p16+ cells comprised 73% to 85% of all detected EPCs in leukemia patients up to 1 year post-treatment, while apoptotic Annexin V+ EPCs ranged from 44% to 57% and remained below healthy control proportions.

Study Design

Type

Cohort (n=48)

Multicenter

No

Structured PICO

Does anthracycline chemotherapy impair endothelial injury and repair biomarkers (CECs and EPCs) and alter EPC cell fate up to 1 year post-treatment in children with leukemia or lymphoma?

P

Population

48 children (<18 years) with leukemia (n=35) or lymphoma (n=13) and normal baseline cardiac function (LVEF >55%) treated with anthracycline-containing chemotherapy at a single center in Singapore, followed up to 1 year post-treatment.

E

Exposure

Anthracycline-containing combination chemotherapy (longitudinal assessment at pre-treatment, ~1-month post-treatment, 3 months post-treatment, and 1 year post-treatment)

C

Comparator

Age-matched healthy controls and pre-treatment baseline measurements

O

Outcome

Longitudinal quantification of circulating endothelial cells (CECs, CD45-/CD31+/CD133-/DNA+) and endothelial progenitor cells (EPCs, CD45-/CD31+/CD133+/DNA+) per 10,000 PBMCs, and EPC fate characterized by senescence (p16+) and apoptosis (Annexin V+) via flow cytometry up to 1 year post-treatmentsurrogate

Long-term endothelial impairment in childhood cancer survivors treated with anthracyclines appears driven by defective endothelial regeneration and high EPC senescence rather than persistent active endothelial injury.

Limitations

Single-centre retrospective cohort design with a small sample size (n=48)
Non-organ-specific nature of circulating endothelial cells (CECs), making it impossible to definitively conclude they originate from the coronary vasculature
Lack of significant clinical cardiomyocyte damage or LVEF decline within the 1-year follow-up period
Single-centre retrospective cohort study
Small sample size (35 leukemia and 13 lymphoma patients)
Non-organ-specific nature of circulating endothelial cells (CECs), limiting the ability to confirm coronary vasculature origin
Lack of significant overt cardiac remodeling or LVEF decline during the 1-year follow-up period

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Implication

Anthracycline-associated EPC senescence may underlie persistent endothelial repair defects in survivors; hypothesis-generating and requires prospective validation before clinical adoption.

Abstract

Background Anthracyclines are central to childhood cancer therapy but predispose patients to cardiotoxicity leading to long-term cardiovascular risk. Endothelial injury and impaired repair contribute to this, yet pediatric data remain limited. Objective To longitudinally assess endothelial injury and repair in childhood cancer patients treated with anthracyclines by quantifying circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs). Methods In a single-centre retrospective cohort, children (<18 years) diagnosed with leukemia (n=35) or lymphoma (n=13) were studied at four timepoints: pre-treatment (“Pre”), ∼1-month- (“End”), 3 months- (3M), and 1 year- (1Y) post-treatment. Peripheral blood mononuclear cells were analyzed by flow cytometry to quantify CECs and EPCs, and EPC fate was assessed by p16 (senescence) and Annexin V (apoptosis). Cardiac injury biomarkers and left ventricular function were assessed at each timepoint. Results Longitudinal trends of CEC and EPC counts were similar between leukemia and lymphoma participants. CECs were highest at pre-treatment and declined significantly thereafter, though they remained marginally elevated during remission compared with healthy controls, indicating that endothelial damage had largely subsided following treatment. EPCs were also highest at pre-treatment and decreased to levels below healthy controls during remission, suggesting impaired baseline endothelial maintenance and repair. Furthermore, EPCs were predominantly senescent up to 1-year post-treatment. Conclusions Endothelial injury resolves by treatment completion, but repair remains impaired during remission with EPC pools dominated by senescent cells. This suggests defective endothelial regeneration, rather than persistent injury, drives long-term cardiovascular complications and underscores the need to restore EPC viability and function in childhood cancer survivors.

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Cite This Study

Markandran et al. (2026) conducted a cohort in Childhood leukemia (n=35) or lymphoma (n=13) (n=48). Anthracycline chemotherapy vs. Age-matched healthy controls and pre-treatment baseline was evaluated on Longitudinal circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), and EPC fate (p16+ senescence and Annexin V+ apoptosis). Anthracycline-treated childhood cancer survivors had decreased endothelial progenitor cells (0.12%-2.6% of PBMCs) dominated by senescent p16+ cells (73%-95%) up to 1 year post-treatment.

synapsesocial.com/papers/6af3b1a5cf860dd505ec1310 https://doi.org/10.3390/cells15212040

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Compromised Endothelial Regeneration as a Potential Contributor to Long-Term Cardiovascular Complications in Childhood Cancer Survivors

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Compromised Endothelial Regeneration as a Potential Contributor to Long-Term Cardiovascular Complications in Childhood Cancer Survivors

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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