Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors

Qipeng Fan, Dongsheng Gu, Hailan Liu, Ling Yang, Xiaoli Zhang, Mervin Yoder, Mark Kaplan, Jingwu Xie

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.

Original languageEnglish
Pages (from-to)471-483
Number of pages13
JournalCancer Research
Volume74
Issue number2
DOIs
StatePublished - Jan 15 2014

Fingerprint

Hedgehogs
Bone Marrow Cells
Skin
Tumor Microenvironment
Neoplasms
Immunosuppressive Agents
CCR2 Receptors
Basal Cell Carcinoma
Myeloid-Derived Suppressor Cells
Keratinocytes
Chemokines
Cell Movement
T-Lymphocytes
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors. / Fan, Qipeng; Gu, Dongsheng; Liu, Hailan; Yang, Ling; Zhang, Xiaoli; Yoder, Mervin; Kaplan, Mark; Xie, Jingwu.

In: Cancer Research, Vol. 74, No. 2, 15.01.2014, p. 471-483.

Research output: Contribution to journalArticle

Fan, Qipeng ; Gu, Dongsheng ; Liu, Hailan ; Yang, Ling ; Zhang, Xiaoli ; Yoder, Mervin ; Kaplan, Mark ; Xie, Jingwu. / Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors. In: Cancer Research. 2014 ; Vol. 74, No. 2. pp. 471-483.
@article{af889518795948ef822a03493461fec0,
title = "Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors",
abstract = "Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.",
author = "Qipeng Fan and Dongsheng Gu and Hailan Liu and Ling Yang and Xiaoli Zhang and Mervin Yoder and Mark Kaplan and Jingwu Xie",
year = "2014",
month = "1",
day = "15",
doi = "10.1158/0008-5472.CAN-13-2134-T",
language = "English",
volume = "74",
pages = "471--483",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors

AU - Fan, Qipeng

AU - Gu, Dongsheng

AU - Liu, Hailan

AU - Yang, Ling

AU - Zhang, Xiaoli

AU - Yoder, Mervin

AU - Kaplan, Mark

AU - Xie, Jingwu

PY - 2014/1/15

Y1 - 2014/1/15

N2 - Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.

AB - Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.

UR - http://www.scopus.com/inward/record.url?scp=84892942306&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892942306&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-13-2134-T

DO - 10.1158/0008-5472.CAN-13-2134-T

M3 - Article

C2 - 24282281

AN - SCOPUS:84892942306

VL - 74

SP - 471

EP - 483

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 2

ER -