Stromal Endothelial Cells Directly Influence Cancer Progression
Science Translational Medicine • 19 Jan 2011 • Vol 3, Issue 66 • p. 66ra5 • DOI: 10.1126/scitranslmed.3001542
Not Just Wallflowers After All
Teen movies like Mean Girls and Never Been Kissed remind us that every school has its wallflowers—kids who are always present, but serve as wallpaper at social functions. Yet, if one takes the time to talk with them, some wallflowers turn out to be the most interesting guests at the gala. Lining the walls of blood vessels, endothelial cells have long been thought to be the wallflowers of tumors—providing support but not having a clearly defined, active role in tumor growth and metastasis. Now, Franses et al. have found that, instead, endothelial cells are the life of the party in the tumor microenvironment, secreting molecules that dynamically regulate cancer cell proliferation and invasiveness.
The authors explored the effects of secretions from quiescent endothelial cells—ones that have exited the cell cycle—on tumors both in vitro and in a mouse model of lung adenocarcinoma. They found that endothelial cells produced molecules that blocked proliferation and invasiveness of both breast and lung cancer cells in vitro, perhaps by reducing signaling through intracellular pro-tumor and pro-inflammatory pathways. Inhibiting endothelial cell production of perlecan, which is a component of the extracellular matrix, blocked this effect on tumor cell invasiveness in a manner that was dependent on the pro-inflammatory cytokine interleukin-6. Indeed, in vivo transplantation of quiescent endothelial cells embedded in a porous matrix curbed tumor growth, and perlecan was required for metastatic inhibition by endothelial secretions. These observations suggest that endothelial cells do not just hang around in the background providing support, but are active participants in and potential targets for regulating the tumor microenvironment. Endothelial cell–cancer interactions add to the emerging appreciation of stromal-cancer crosstalk, and may enable exciting, novel therapies for malignant diseases.
Abstract
Cancer growth and metastasis are regulated in part by stromal cells such as fibroblasts and immune cells within the tumor microenvironment. Endothelial cells (ECs) are also ubiquitous within tumors because tumors are vascular, and yet, the impact of tumor-resident ECs is less well understood. Through paracrine regulation, ECs modulate a diverse spectrum of pathophysiologic processes in normal and hyperplastic tissues. We hypothesized that ECs offer similar paracrine regulatory control of cancer biology. Indeed, secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling. EC perlecan silencing significantly changed this regulatory relationship, eliminating the ability of ECs to inhibit cancer cell invasiveness via increased interleukin-6 secretion. Moreover, implanting ECs embedded within porous matrices slowed adjacent xenograft tumor growth and prevented architectural degeneration, with a concomitant reduction in proliferative and tumorigenic markers. Finally, lung carcinoma cells pretreated with intact EC-conditioned media, but not media conditioned with perlecan-silenced ECs, exhibited reduced micrometastatic burden after tail vein injection. These findings add to an emerging appreciation of EC-regulatory effects that transcend their structural roles and pave the way for improved characterization and control of EC-cancer cross-talk interactions for diagnosis, prognosis, and treatment of cancer.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Long-term culture of cancer cells in endothelial cell–conditioned media slows cell growth.
Fig. S2. Although the secretome of ECs contains a large amount of latent MMP2, it inhibits significantly cancer cell invasiveness.
Fig. S3. Media conditioned by normal fibroblasts have no effect on cancer cell proliferation or invasiveness.
Fig. S4. Inhibition of one signaling pathway in cancer cells cannot recapitulate EC-mediated regulation of cancer cells.
Fig. S5. Description of perlecan silencing on EC phenotype.
Fig. S6. Further studies of the perlecan/IL-6 axis in endothelial cells and its role in the regulation of cancer cell invasiveness.
Fig. S7. MEECs are phenotypically similar to ECs.
Fig. S8. Representative Ki-67 and S6RP staining in control and MEEC-treated A549 xenograft tumors.
Fig. S9. H&E-stained sections from each tumor showing intratumoral cysts.
Table S1. List of primers used for qRT-PCR.
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Information & Authors
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Published In
Science Translational Medicine
Volume 3 | Issue 66
January 2011
January 2011
Copyright
Copyright © 2011, American Association for the Advancement of Science.
Submission history
Received: 30 July 2010
Accepted: 17 December 2010
Acknowledgments
Acknowledgments: We thank E. Abraham for his experimental and technical advice and B. King for her help with the experimental metastasis model. Funding: Supported by NIH grant R01 GM49039 to E.R.E., NIH Medical Scientist Training Program funding for J.W.F., American Heart Association Scientist Development grant 2630129 to A.B.B., and NIH–National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK080946) and National Kidney Foundation Young Investigator Grant Award to V.C.C. Author contributions: J.W.F. helped conceive of and performed all experiments and data analysis and wrote the manuscript. A.B.B. aided in certain animal experiments and helped in editing the manuscript. V.C.C. aided in the perlecan silencing experiments and helped in editing the manuscript. E.R.E. conceived of and supervised all experiments and the writing of the manuscript. Competing interests: E.R.E. and J.W.F. are co-inventors on a patent application owned by Massachusetts Institute of Technology that describes the use of cell implants to modulate cancer behavior. E.R.E. is a founder of Pervasis Therapeutics, which has licensed the patent application. No other authors have competing interests to declare.
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