Linear Versus Parallel Metastatic Progression of Urological Cancers - Expert Commentary

The two most prevailing models of metastatic progression are the linear and parallel models. The linear model predicts genetic and epigenetic alterations and tumor fitness. Once a founder cell gains a metastatic phenotype, the invasion-metastasis cascade begins. On the other hand, the parallel model suggests preclinical tumor cell distribution followed by selection and expansion occurring at distant organs.

A recent study by Gofrit et al. examined these models using retrospective analysis of the radiological patterns in patients with lung metastases. They hypothesized that tumors with linear metastases patterns are expected to have comparable diameters in any specific organ due to identical clonal origin and similar timing of metastases. In contrast, parallel metastases are expected to have variable sizes and calculated the linear to parallel ratio. The authors measured 12,887 metastases in 503 patients with nine malignancy types, including several tumor types, including renal cell, prostate, and bladder cancers. In carcinomas of the pancreas, prostate, and thyroid, the median LPR was 1. Median LPRs were 0.91, 0.65, 0.60, 0.58, 0.50 and 0.43 in renal cell carcinomas, melanomas, colorectal, breast, bladder, and sarcomas, respectively.

These data suggest that prostate cancers spread almost exclusively through the linear route. In contrast, the spread of kidney, melanoma, colorectal, breast, bladder, and sarcoma is both linear and parallel, with the increasing dominance of the parallel route in this order. These data are consistent with previous work characterizing the clonal evolution of bladder cancer, showing early clonal divergence and metastatic spread.1 Understanding metastases pattern is critical for identifying interception strategies to prevent distant spread.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nature Genetics. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.3692. Epub 2016 Oct 17.

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