title: Malignant cells facilitate lung metastasis by bringing their own soil.
abstract: Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil--stromal components including activated fibroblasts--from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated in heterotypic tumor-stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic cancer cells, significantly decreases the number of metastases and extends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has important conceptual and clinical implications for the colonization step in tumor progression.
authors.affiliation: Edwin L Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Annique M M J
authors.initials: AM
authors.lastname: Duyverman
authors.forename: Mitsutomo
authors.initials: M
authors.lastname: Kohno
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology*
chemical_list: D011993:Recombinant Fusion Proteins