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Investigating structural associations of the lymphatic vasculature in Wilms tumour
Daniyal J. Jafree, PhD1, Kevin X. Cao, MBBS MRCS MSc1, Reem Al-Saadi, MSc PhD2, Guillaume Morcrette, PhD2, Tanzina Chowdhury, MBBS2, Aleksandra Letunovska, MSc2, Cheuk Y. Man, MSc1, Navroop S. Johal, MB BCh FRCS PhD2, Paul J. Winyard, BM BCh FRCPCH PhD1, Peter J. Scambler, MBBS PhD1, Kathy Pritchard-Jones, BM BCh PhD2, David A. Long, PhD1.
1UCL Great Ormond Street Institute of Child Health, London, United Kingdom, 2Great Ormond Street Hospital for Children, London, United Kingdom.

BACKGROUND:
The lymphatic vasculature maintains tissue fluid balance and mediates the resolution of inflammation in health and disease. However, there are conflicting views regarding its role in the microenvironment of malignancy. Lymphatic infiltration in some solid tumours is associated with metastatic spread, whilst in other cases, lymphatics may modulate protective anti-tumour immune surveillance. There is very little information on the role of lymphatic vessels in childhood kidney cancer; one of the most common solid tumours in children. Here, we use emerging technologies to examine the lymphatic vessel network in Wilms' tumour, the most prevalent childhood kidney cancer.
METHODS:
Tissue volumes were subsampled from nephrectomies for Wilms tumours and adjacent non-tumorous renal tissue, as part of the international UMBRELLA study. All tumours had been subject to a course of pre-operative chemotherapy as per SIOP treatment guidelines. Specimens were fixed in paraformaldehyde before proceeding through wholemount immunofluorescence and optical clearing to enable three-dimensional imaging of lymphatic vasculature. We compared three-dimensional images for the presence of lymphatic vessels as well as their diameter and vessel density, defined as the number of lymphatic vessel branches per unit volume of tissue.
RESULTS:
These techniques demonstrated that after chemotherapy, lymphatic infiltration continues to be a feature of Wilms' tumour. Lymphatic density was greater within the tumour microenvironment than adjacent non-tumorous kidney tissue or kidneys without malignancy. Distinct lymphatic patterns were observed dependent on tumour subtype, with greater tumour lymphatic density and smaller vessel diameter observed in epithelial-predominant Wilms tumours compared to stromal-predominant regions. In ongoing work, we are employing computational interrogation of transcriptomics datasets to complement our imaging findings and assess how the lymphatic transcriptome varies with clinical outcome.
CONCLUSIONS:

These results suggest that lymphatic infiltration is a feature of the Wilms' tumour microenvironment after chemotherapy. Comparative evaluation of lymphatic structure in pre-chemotherapy tumours (NWTS protocol) will help to elaborate if lymphatic infiltration is a cellular hallmark of the response to chemotherapy. This could suggest the lymphatic system has a role in post-chemotherapy organ recovery, or an indicator of its role in the primary disease. Further, the observed variation in lymphatic density by histological risk group could provide a rationale to investigate lymphatic-derived molecules as prognostic biomarkers for Wilms tumour. Ultimately, our ongoing work may yield insights to harness the lymphatic vasculature to enhance targeted treatments, such as immunotherapy, for Wilms' tumour and other renal cancers.


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