Imaging Tumor-stroma Interactions During Chemotherapy Reveals Contributions of the Microenvironment to Resistance

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2012 Apr 21

PMID 22516258

Citations 262

Authors

Elizabeth S Nakasone

Hanne A Askautrud

Tim Kees

Jae-Hyun Park

Vicki Plaks

Andrew J Ewald

Miriam Fein

Morten G Rasch

Ying-Xim Tan

Jing Qiu

Juwon Park

Pranay Sinha

Mina J Bissell

Eirik Frengen

Zena Werb

Mikala Egeblad

Affiliations

Soon will be listed here.

Abstract

Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.

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References

Egeblad M, Nakasone E, Werb Z . Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010; 18(6):884-901. PMC: 2905377. DOI: 10.1016/j.devcel.2010.05.012. View

Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M . Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009; 125(6):1276-84. DOI: 10.1002/ijc.24378. View

Olive K, Jacobetz M, Davidson C, Gopinathan A, McIntyre D, Honess D . Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324(5933):1457-61. PMC: 2998180. DOI: 10.1126/science.1171362. View

Tsou C, Peters W, Si Y, Slaymaker S, Aslanian A, Weisberg S . Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007; 117(4):902-9. PMC: 1810572. DOI: 10.1172/JCI29919. View

Rasch M, Lund I, Illemann M, Hoyer-Hansen G, Gardsvoll H . Purification and characterization of recombinant full-length and protease domain of murine MMP-9 expressed in Drosophila S2 cells. Protein Expr Purif. 2010; 72(1):87-94. DOI: 10.1016/j.pep.2010.03.002. View

Yu Q, Stamenkovic I . Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000; 14(2):163-76. PMC: 316345. View

Martin M, Carter K, Jean-Philippe S, Chang M, Mobashery S, Thiolloy S . Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background. Cancer Res. 2008; 68(15):6251-9. PMC: 2789265. DOI: 10.1158/0008-5472.CAN-08-0537. View

Sadik C, Kim N, Luster A . Neutrophils cascading their way to inflammation. Trends Immunol. 2011; 32(10):452-60. PMC: 3470857. DOI: 10.1016/j.it.2011.06.008. View

Gong Y, Hart E, Shchurin A, Hoover-Plow J . Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest. 2008; 118(9):3012-24. PMC: 2491456. DOI: 10.1172/JCI32750. View

10.

Thurston G, Suri C, Smith K, McClain J, Sato T, Yancopoulos G . Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science. 2000; 286(5449):2511-4. DOI: 10.1126/science.286.5449.2511. View

11.

Herschkowitz J, Simin K, Weigman V, Mikaelian I, Usary J, Hu Z . Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007; 8(5):R76. PMC: 1929138. DOI: 10.1186/gb-2007-8-5-r76. View

12.

Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2006; 13(1):54-61. DOI: 10.1038/nm1523. View

13.

Gilbert L, Hemann M . DNA damage-mediated induction of a chemoresistant niche. Cell. 2010; 143(3):355-66. PMC: 2972353. DOI: 10.1016/j.cell.2010.09.043. View

14.

Minchinton A, Tannock I . Drug penetration in solid tumours. Nat Rev Cancer. 2006; 6(8):583-92. DOI: 10.1038/nrc1893. View

15.

Pahler J, Tazzyman S, Erez N, Chen Y, Murdoch C, Nozawa H . Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia. 2008; 10(4):329-40. PMC: 2288539. DOI: 10.1593/neo.07871. View

16.

Zhang J, Lu Y, Pienta K . Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010; 102(8):522-8. PMC: 2857800. DOI: 10.1093/jnci/djq044. View

17.

Netti P, Hamberg L, Babich J, Kierstead D, GRAHAM W, Hunter G . Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A. 1999; 96(6):3137-42. PMC: 15908. DOI: 10.1073/pnas.96.6.3137. View

18.

Dean M, Fojo T, Bates S . Tumour stem cells and drug resistance. Nat Rev Cancer. 2005; 5(4):275-84. DOI: 10.1038/nrc1590. View

19.

Goel S, Duda D, Xu L, Munn L, Boucher Y, Fukumura D . Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011; 91(3):1071-121. PMC: 3258432. DOI: 10.1152/physrev.00038.2010. View

20.

Ahn G, Tseng D, Liao C, Dorie M, Czechowicz A, Brown J . Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci U S A. 2010; 107(18):8363-8. PMC: 2889597. DOI: 10.1073/pnas.0911378107. View