title: Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma.
abstract: Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the 'seed and soil' hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF-A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF-A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p < 0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF-A-expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF-A-induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis.
authors.affiliation: Department of Pathology, Radboud University, Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Gursah
authors.initials: G
authors.lastname: Kats-Ugurlu
authors.forename: Ilse
authors.initials: I
authors.lastname: Roodink
authors.forename: Mirjam
authors.initials: M
authors.lastname: de Weijert
authors.forename: Dorien
authors.initials: D
authors.lastname: Tiemessen
authors.forename: Cathy
authors.initials: C
authors.lastname: Maass
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.forename: Jeroen
authors.initials: J
authors.lastname: van der Laak
authors.forename: Rob
authors.initials: R
authors.lastname: de Waal
authors.forename: Peter
authors.initials: P
authors.lastname: Mulders
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: William
authors.initials: W
authors.lastname: Leenders
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A