Zebrafish Cervical Cancer Models

Introduction

Cervical cancer is a malignancy arising from the cervix, the lower portion of the uterus. It is the fifth most commonly diagnosed cancer in women globally, with approximately 604,000 new cases and 280,000 deaths reported in 2024. Persistent infection with high-risk human papillomavirus (HPV) subtypes—primarily HPV16 and HPV18—accounts for over 95% of cases. Histologically, squamous cell carcinoma represents ~80–85% of cervical cancers, while adenocarcinoma comprises the majority of the remainder. Early-stage disease is often asymptomatic; advanced disease presents with abnormal vaginal bleeding, pelvic pain, and postcoital bleeding. The disease disproportionately affects women in low- and middle-income countries, where screening and vaccination coverage remain limited. Prognosis is highly stage-dependent: five-year survival exceeds 90% for localized disease but drops below 20% for metastatic cervical cancer.

Current standard of care includes HPV prophylactic vaccination, surgical resection (conization, trachelectomy, hysterectomy), radiotherapy with concurrent platinum-based chemotherapy, and, more recently, immune checkpoint inhibitors (pembrolizumab) and antibody-drug conjugates (tisotumab vedotin) for recurrent/metastatic disease. However, therapeutic resistance, tumor recurrence, and metastatic progression remain significant clinical challenges. Preclinical models that recapitulate key aspects of cervical cancer biology—including tumor–host interactions, angiogenesis, and metastatic dissemination—are needed to accelerate drug discovery and translational research. Zebrafish models have emerged as a valuable platform for cervical cancer xenograft studies, enabling high-throughput drug screening, real-time visualization of tumor cell behavior, and in vivo assessment of anti-angiogenic and anti-metastatic agents.

Why Zebrafish?

• Optical Transparency: Optical transparency enables real-time imaging of tumor engraftment, angiogenesis, and metastasis.
• High Fecundity: High fecundity supports medium-to-high-throughput drug screening with robust sample sizes within days.
• Conserved Cancer Biology: Conserved cancer biology—p53, Rb, and angiogenic pathways are functionally conserved in zebrafish.
• Minimal Compound Requirement: Minimal compound requirements reduce drug quantity needs for early pharmacokinetic and toxicity profiling.
• Immunocompromised Lines: Immunocompromised lines (e.g., rag2 mutants) permit human cervical cancer cell engraftment without rejection.

Available Zebrafish Disease Models

Our cervical cancer platform spans HPV-positive and HPV-negative cell line xenografts, adult immunocompromised models, and HPV transgenic models:

Phenotypic Evaluation

Key Applications

• Anti-cervical Cancer Drug Screening: Evaluate antiproliferative, pro-apoptotic, and anti-angiogenic activity of small molecules, biologics, and natural products against human cervical cancer cell lines in vivo.
• Anti-angiogenic Agent Evaluation: Assess candidate compounds targeting VEGF/VEGFR, FGF, and other angiogenic pathways using tumor-induced neovascularization readouts in transgenic vascular reporter lines.
• Metastasis and Invasion Studies: Track tumor cell dissemination, extravasation, and colonization in real time to identify anti-metastatic compounds or validate metastasis-associated gene targets.
• HPV Oncogene Mechanistic Studies: Investigate the role of HPV E6/E7 oncoproteins in tumor initiation, epithelial-mesenchymal transition, and host immune evasion using transgenic zebrafish lines.
• Combination Therapy and Resistance Modeling: Test synergistic effects of chemotherapy–immunotherapy combinations (e.g., cisplatin + pembrolizumab) and characterize mechanisms of acquired drug resistance.

Study Examples

Fluorescently labeled HeLa cells (HPV18+ cervical adenocarcinoma) were microinjected into the perivitelline space of 48 hpf Tg(fli1:EGFP) zebrafish embryos, which express EGFP in all vascular endothelial cells. Tumor cell engraftment was confirmed at 24 hpi, and tumor-induced subintestinal vessel (SIV) sprouting was quantified by confocal microscopy.

Fig. 1. HeLa xenografts induce robust angiogenic sprouting of subintestinal vessels in zebrafish embryos, which is suppressed by VEGFR inhibition (Liu C, Zhang Y, et al., 2018).

Reference

1. Liu C, Zhang Y, et al. (2019). A zebrafish model discovers a novel mechanism of stromal fibroblast-mediated breast cancer metastasis to the brain. Cancer Research 79(13 Suppl): Abstract 2018.