Editors' ChoiceCancer

Tumor cell dispersal: A little movement goes a long way

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Science Translational Medicine  09 Sep 2015:
Vol. 7, Issue 304, pp. 304ec155
DOI: 10.1126/scitranslmed.aad3070

Human tumors display a surprising paucity of mutations when compared with an equivalent mass of normal cells. Remarkably, even within large tumors, the majority of mutations, especially driver mutations, are contained within most neoplastic cells, and genetic heterogeneity is limited. This phenomenon was previously not well understood. Waclaw et al. now use a model combining spatial growth and genetic evolution to show that short-range tumor cell dispersal has a substantial impact on key tumor-related phenomena, including growth, development of resistance to chemotherapy, and genetic heterogeneity.

The ability of tumor cells to migrate has been viewed as a late event in tumorigenesis, where long-distance migration contributes to the process of metastasis. In their model, Waclaw et al. show in primary tumors that short-range dispersal combined with a minimal selective growth advantage allows malignant cells within an established tumor to overtake other populations, leading to a marked decrease in the genetic diversity. The authors based their model on metastatic tumors, where histopathology suggests that cell proliferation is greater at the edge of a lesion compared with its center. Then, they applied this to their model so that the rate of replication was proportional to the number of surrounding sites not containing malignant cells. Introducing any amount of cell dispersal converted the tumor growth pattern from a sphere to a sprouting conglomerate of “balls” interspersed with nonmalignant tissue, closely resembling actual metastatic lesions. Dispersal also had a strong effect on the growth rate of metastases in the absence of any changes in cell net growth rates, shortening the predicted time it would take for 1 cell to grow into 107 cells from 8 years, in the absence of dispersal, to under 2 years, consistent with experimental and clinical experience. Indeed, dispersal increases the probability of regrowth after treatment, especially for more aggressive cancers. If resistant mutations happen to increase dispersal, regrowth is also predicted to be faster.

Although models suffer from the necessity of making multiple assumptions and oversimplifications, the predictions made by the spatial-genetic model proposed by Waclaw et al. better correlate to known clinical observations compared with existing models. This model offers a compelling argument for the importance of short-range tumor cell dispersal in hitherto poorly understood tumor related phenomenon, and identifies dispersal related genes as potential therapeutic targets.

B. Waclaw et al., A spatial model predicts that dispersal and cell turnover limit intratumor heterogeneity. Nature 10.1038/nature14971 (2015). [Abstract]

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