Malignant cells facilitate lung metastasis by bringing their own soil
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a preclinical model of tumor progression, the presence of fibroblasts enhanced the survival of circulating tumor cells, facilitating their colonization at distant sites following primary tumor dissemination.
“In a preclinical model of tumor progression, the presence of fibroblasts enhanced the survival of circulating tumor cells, facilitating their colonization at distant sites following primary tumor dissemination [41].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [41]
Depletion of CAFs significantly reduced metastatic burden and extended survival following tumor resection.
“Notably, depletion of CAFs significantly reduced metastatic burden and extended survival following tumor resection [41].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [41]
Cites
The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited
Fidler, I. J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1098 · Cited by 4,686 · see citing works
OʼReilly, M. (1994) · Cell · doi:10.1016/0092-8674(94)90200-3 · Cited by 3,344 · see citing works
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., et al. (2005) · Nature · doi:10.1038/nature04186 · Cited by 3,288 · see citing works
Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells
Wagers, A. J., Sherwood, R. I., Christensen, J. L., & Weissman, I. L. (2002) · Science · doi:10.1126/science.1074807 · Cited by 1,460 · see citing works
AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective
Talmadge, J. E., & Fidler, I. J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1040 · Cited by 1,172 · see citing works
Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis
Kim, S., Takahashi, H., Lin, W.-W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J.-L., & Karin, M. (2009) · Nature · doi:10.1038/nature07623 · Cited by 1,100 · see citing works
Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., & Shibuya, M. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00153-8 · Cited by 910 · see citing works
Cancer cells compress intratumour vessels
Padera, T. P., Stoll, B. R., Tooredman, J. B., Capen, D., Tomaso, E. D., & Jain, R. K. (2004) · Nature · doi:10.1038/427695a · Cited by 857 · see citing works
Self-citationAl‐Mehdi, A., Tozawa, K., Fisher, A. B., Shientag, L., Lee, A., & Muschel, R. J. (2000) · Nature Medicine · doi:10.1038/71429 · Cited by 703 · see citing works
The significance of hematogenous tumor cell clumps in the metastatic process.
Liotta, L. A., Saidel, M. G., & Kleinerman, J. I. (1976) · PubMed · Cited by 572 · see citing works
Illuminating the metastatic process
Sahai, E. A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2229 · Cited by 566 · see citing works
Fidler, I. J. (1973) · European Journal of Cancer (1965) · doi:10.1016/s0014-2964(73)80022-2 · Cited by 411 · see citing works
Role of Pancreatic Stellate Cells in Pancreatic Cancer Metastasis
Xu, Z., Vonlaufen, A., Phillips, P. A., Fiala‐Beer, E., Zhang, X., Yang, L., Biankin, A. V., Goldstein, D., Pirola, R. C., Wilson, J. S., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090899 · Cited by 356 · see citing works
Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung
Podsypanina, K., Du, Y. N., Jechlinger, M., Beverly, L. J., Hambardzumyan, D., & VARMUS, H. E. (2008) · Science · doi:10.1126/science.1161621 · Cited by 300 · see citing works
Duda, D. G., Cohen, K. S., Kozin, S. V., Perentes, J. Y., Fukumura, D., Scadden, D. T., & Jain, R. K. (2005) · Blood · doi:10.1182/blood-2005-08-3210 · Cited by 140 · see citing works
Self-citationUpdyke, T. V., & Nicolson, G. L. (1986) · Clinical & Experimental Metastasis · doi:10.1007/bf00133592 · Cited by 91 · see citing works
Swartz, M. A., Kristensen, C. A., Melder, R. J., et al. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690760 · Cited by 67 · see citing works
van Deventer, H. W., Wu, Q., Bergstralh, D. T., Davis, B. K., O’Connor, B. P., Ting, J. P. ‐., & Serody, J. S. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070732 · Cited by 63 · see citing works
Differential Transplantability of Tumor-Associated Stromal Cells
Duda, D. G., Fukumura, D., Munn, L. L., Booth, M. F., Brown, E. B., Huang, P., Seed, B., & Jain, R. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1268 · Cited by 50 · see citing works
Self-citationHuang, P., Duda, D. G., Jain, R. K., & Fukumura, D. (2008) · PubMed Central · Cited by 43 · see citing works
Self-citationTissue-Isolated Human Tumor Xenografts in Athymic Nude Mice
Kristjansen, P. E. G., Roberge, S., Lee, I., et al. (1994) · Microvascular Research · doi:10.1006/mvre.1994.1063 · Cited by 37 · see citing works
Tumour metastasis: is tissue an issue?
Ruiter, D. J., Krieken, J. H. J. M. V., van Muijen, G. N., et al. (2001) · The Lancet Oncology · doi:10.1016/s1470-2045(00)00229-1 · Cited by 37 · see citing works
Arbiser, J. L., Raab, G., Rohan, R. M., Paul, S., Hirschi, K. K., Flynn, E. A., Price, E. R., Fisher, D. E., Cohen, C., & Klagsbrun, M. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65171-1 · Cited by 36 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · see citing works
Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition
Yu, M., Bardia, A., Wittner, B. S., Stott, S. L., Smas, M. E., Ting, D. T., Isakoff, S. J., Ciciliano, J. C., Wells, M. N., Shah, A. M., et al. (2013) · Science · doi:10.1126/science.1228522 · Cited by 2,476 · see citing works
Diversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265 · see citing works
Recent Developments in Myofibroblast Biology
Hinz, B., Phan, S. H., Thannickal, V. J., Prunotto, M., Desmoulière, A., Varga, J., De Wever, O., Mareel, M., & Gabbiani, G. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.02.004 · Cited by 1,193 · see citing works
Anoikis molecular pathways and its role in cancer progression
Paoli, P., Giannoni, E., & Chiarugi, P. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.026 · Cited by 1,160 · see citing works
Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
Stylianopoulos, T., Martin, J. D., Chauhan, V. P., Jain, S. R., Diop-Frimpong, B., Bardeesy, N., Smith, B. L., Ferrone, C. R., Hornicek, F. J., Boucher, Y., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213353109 · Cited by 943 · see citing works
Self-citationThe biology of brain metastases—translation to new therapies
Eichler, A. F., Chung, E., Kodack, D. P., Loeffler, J. S., Fukumura, D., & Jain, R. K. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.58 · Cited by 567 · see citing works
Self-citationNormalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges
Martin, J. D., Seano, G., & Jain, R. K. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114700 · Cited by 530 · see citing works
Self-citationChen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P., Huang, P., Lindeman, N., Langer, R., & Jain, R. K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815515116 · Cited by 406 · see citing works
Self-citationMetastasis-Initiating Cells and Ecosystems
Massagué, J., & Ganesh, K. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0010 · Cited by 372 · see citing works
Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not?
De Bock, K., Mazzone, M., & Carmeliet, P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.83 · Cited by 293 · see citing works
Carcinoma‐associated fibroblasts: Non‐neoplastic tumour‐promoting mesenchymal cells
Polanska, U. M., & Orimo, A. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24347 · Cited by 208 · see citing works
Elgundi, Z., Papanicolaou, M., Major, G., Cox, T. R., Melrose, J., Whitelock, J. M., & Farrugia, B. L. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01482 · Cited by 176 · see citing works
Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy
Raskov, H., Orhan, A., Gaggar, S., & Gögenur, I. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.668731 · Cited by 150 · see citing works
Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells
Bonuccelli, G., Avnet, S., Grisendi, G., Salerno, M., Granchi, D., Dominici, M., Kusuzaki, K., & Baldini, N. (2014) · Oncotarget · doi:10.18632/oncotarget.2243 · Cited by 140 · see citing works
Circulating Tumor Cells: Fluid Surrogates of Solid Tumors
Thiele, J.-A., Bethel, K., Králíčková, M., & Kuhn, P. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100256 · Cited by 107 · see citing works
Shah, S., & D’Souza, G. G. M. (2025) · Cells · doi:10.3390/cells14100732 · Cited by 66 · see citing works
“In a preclinical model of tumor progression, the presence of fibroblasts enhanced the survival of circulating tumor cells, facilitating their colonization at distant sites following primary tumor dissemination [41].”
Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review)
Naser, R., Fakhoury, I., El‑Fouani, A., Abi‑Habib, R., & El‑Sibai, M. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5471 · Cited by 61 · see citing works
Co-migration of colon cancer cells and CAFs induced by TGFβ₁ enhances liver metastasis
Gonzalez-Zubeldia, I., Dotor, J., Redrado, M., Bleau, A.-M., Manrique, I., de Aberasturi, A. L., Villalba, M., & Calvo, A. (2015) · Cell and Tissue Research · doi:10.1007/s00441-014-2075-6 · Cited by 51 · see citing works
Pre-clinical Models of Metastasis in Pancreatic Cancer
Miquel, M., Zhang, S., & Pilarsky, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.748631 · Cited by 53 · see citing works
Ramundo, V., Zanirato, G., & Aldieri, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212216 · Cited by 46 · see citing works
Senescence and the Pro-tumorigenic Stroma
Alspach, E., Fu, Y., & Stewart, S. A. (2013) · Critical Reviews in Oncogenesis · doi:10.1615/critrevoncog.2014010630 · Cited by 47 · see citing works
- Authors
- Duda, D. G., Duyverman, A. M. M. J., Kohno, M., Snuderl, M., Steller, E. J. A., Fukumura, D., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-11-22
- Volume
- 107
- Issue
- 50
- Pages
- 21677-21682
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3003109
- OpenAlex
- W1992944027
- Cited by
- 594
- References
- 23
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 24 · 2023: 47 · 2022: 46 · 2021: 61 · 2020: 61 · 2019: 43 · 2018: 33 · 2017: 33 · 2016: 37 · 2015: 45 · 2014: 34 · 2013: 33 · 2012: 37
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (W81XWH)
- National Institutes of Health (W81XWH)
- National Cancer Institute (R01CA115767, T32CA073479, R01CA085140, R01CA096915, R24CA085140, P01CA080124, R01CA126642)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- lung metastasis, cancer-associated fibroblasts, tumor microenvironment, stromal cells, circulating tumor cells, tumor stroma, brain metastases, lung cancer, metastatic colonization, tumor progression
- MeSH terms
- Animals, Brain Neoplasms, Cell Survival, Fibroblasts, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Transplantation, Recombinant Fusion Proteins, Mice, SCID, Stromal Cells, Disease Progression, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
