JongWook Hong1, Nicholas P Tobin1, Helene Rundqvist1, Tian Li1, Marion Lavergne1, Yaiza García-Ibáñez1, Hanyu Qin1, Janna Paulsson1, Manuel Zeitelhofer1, Milena Z Adzemovic1, Ingrid Nilsson1, Pernilla Roswall1, Johan Hartman1, Randall S Johnson1, Arne Östman1, Jonas Bergh1, Mirjana Poljakovic1, Guillem Genové2. 1. Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ). 2. Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ). guillem.genove@ki.se.
Abstract
BACKGROUND: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. METHODS: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. RESULTS: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). CONCLUSIONS: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.
BACKGROUND: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. METHODS: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancerpatients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. RESULTS: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from humanbreast cancerpatients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). CONCLUSIONS: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.
Authors: Ana E Paiva; Luiza Lousado; Daniel A P Guerra; Patrick O Azevedo; Isadora F G Sena; Julia P Andreotti; Gabryella S P Santos; Ricardo Gonçalves; Akiva Mintz; Alexander Birbrair Journal: Cancer Res Date: 2018-05-22 Impact factor: 12.701
Authors: Joao Incio; Jennifer A Ligibel; Daniel T McManus; Priya Suboj; Keehoon Jung; Kosuke Kawaguchi; Matthias Pinter; Suboj Babykutty; Shan M Chin; Trupti D Vardam; Yuhui Huang; Nuh N Rahbari; Sylvie Roberge; Dannie Wang; Igor L Gomes-Santos; Stefan B Puchner; Christopher L Schlett; Udo Hoffmman; Marek Ancukiewicz; Sara M Tolaney; Ian E Krop; Dan G Duda; Yves Boucher; Dai Fukumura; Rakesh K Jain Journal: Sci Transl Med Date: 2018-03-14 Impact factor: 17.956
Authors: Daniel A P Guerra; Ana E Paiva; Isadora F G Sena; Patrick O Azevedo; Walison N Silva; Akiva Mintz; Alexander Birbrair Journal: Angiogenesis Date: 2018-05-14 Impact factor: 9.596