RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis
Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target...
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Published in | Cancer research (Chicago, Ill.) Vol. 73; no. 1; pp. 50 - 61 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Philadelphia, PA
American Association for Cancer Research
01.01.2013
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Abstract | Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. |
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AbstractList | Abstract
Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. Cancer Res; 73(1); 50–61. ©2012 AACR. Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo , RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. |
Author | PERRUZZI, Carole BRAVO-NUEVO, Arturo BROWN, Lawrence F MANGIANTE, Lee O'DONNELL, Rebekah K KAZEROUNIAN, Shiva TOKER, Alex SHECHTER, Sharon PRENDERGAST, George C MINZHOU HUANG GERALD, Damien MCNAMARA, Stephanie NINGNING ZHENG POURAT, Jacob KOCHER, Olivier N PHUNG, Thuy L BENJAMIN, Laura E UDAYAKUMAR, Durga DUHADAWAY, James B REBECCA CHIN, Y |
AuthorAffiliation | 3 Department of Pathology, Anatomy and Cell Biology and Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University, Philadelphia, Pennsylvania 2 Lankenau Institute for Medical Research, Wynnewood 1 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 4 ImClone Systems, Eli Lilly and Company, New York, New York |
AuthorAffiliation_xml | – name: 3 Department of Pathology, Anatomy and Cell Biology and Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University, Philadelphia, Pennsylvania – name: 1 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts – name: 4 ImClone Systems, Eli Lilly and Company, New York, New York – name: 2 Lankenau Institute for Medical Research, Wynnewood |
Author_xml | – sequence: 1 givenname: Shiva surname: KAZEROUNIAN fullname: KAZEROUNIAN, Shiva organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 2 givenname: Damien surname: GERALD fullname: GERALD, Damien organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 3 givenname: Thuy L surname: PHUNG fullname: PHUNG, Thuy L organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 4 givenname: Arturo surname: BRAVO-NUEVO fullname: BRAVO-NUEVO, Arturo organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 5 givenname: Sharon surname: SHECHTER fullname: SHECHTER, Sharon organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 6 givenname: Stephanie surname: MCNAMARA fullname: MCNAMARA, Stephanie organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 7 givenname: James B surname: DUHADAWAY fullname: DUHADAWAY, James B organization: Lankenau Institute for Medical Research, Wynnewood, United States – sequence: 8 givenname: Olivier N surname: KOCHER fullname: KOCHER, Olivier N organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 9 givenname: Lawrence F surname: BROWN fullname: BROWN, Lawrence F organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 10 givenname: Alex surname: TOKER fullname: TOKER, Alex organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 11 givenname: George C surname: PRENDERGAST fullname: PRENDERGAST, George C organization: Lankenau Institute for Medical Research, Wynnewood, United States – sequence: 12 givenname: Laura E surname: BENJAMIN fullname: BENJAMIN, Laura E organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 13 surname: MINZHOU HUANG fullname: MINZHOU HUANG organization: Lankenau Institute for Medical Research, Wynnewood, United States – sequence: 14 givenname: Y surname: REBECCA CHIN fullname: REBECCA CHIN, Y organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 15 givenname: Durga surname: UDAYAKUMAR fullname: UDAYAKUMAR, Durga organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 16 surname: NINGNING ZHENG fullname: NINGNING ZHENG organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 17 givenname: Rebekah K surname: O'DONNELL fullname: O'DONNELL, Rebekah K organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 18 givenname: Carole surname: PERRUZZI fullname: PERRUZZI, Carole organization: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States – sequence: 19 givenname: Lee surname: MANGIANTE fullname: MANGIANTE, Lee organization: ImClone Systems, Eli Lilly and Company, New York, New York, United States – sequence: 20 givenname: Jacob surname: POURAT fullname: POURAT, Jacob organization: ImClone Systems, Eli Lilly and Company, New York, New York, United States |
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Keywords | Endothelial cell Control Akt protein kinase Breast Tumorigenicity Stromal cell Mammary gland Carcinogenesis Tumor cell Tumor suppressor gene |
Language | English |
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Notes | D. Gerald and M. Huang contributed equally to this work. |
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Snippet | Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports... Abstract Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential... |
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SubjectTerms | Animals Antineoplastic agents Biological and medical sciences Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinoma, Ductal, Breast - metabolism Carcinoma, Ductal, Breast - pathology Cell Transformation, Neoplastic - metabolism Endothelial Cells - metabolism Female Flow Cytometry Gene Expression Regulation, Neoplastic Humans Immunoblotting Immunohistochemistry Immunoprecipitation In Situ Hybridization Medical sciences Mice Mice, Transgenic Neovascularization, Pathologic - metabolism Pharmacology. Drug treatments Proto-Oncogene Proteins c-akt - metabolism Real-Time Polymerase Chain Reaction rhoB GTP-Binding Protein - metabolism Stromal Cells - metabolism Tumor Microenvironment - physiology Tumors |
Title | RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis |
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