Activation of urokinase plasminogen activator and its receptor axis is essential for macrophage infiltration in a prostate cancer mouse model

Jian Zhang, Sudha Sud, Kosuke Mizutani, Margaret R. Gyetko, Kenneth Pienta

Research output: Contribution to journalArticle

Abstract

Macrophages within the tumor microenvironment promote angiogenesis, extracellular matrix breakdown, and tumor cell migration, invasion, and metastasis. Activation of the urokinase plasminogen activator (uPA) and its receptor (uPAR) axis promotes prostate cancer tumorigenicity, invasion, metastasis, and survival within the tumor microenvironment. The link between macrophage infiltration and the uPA/uPAR axis in prostate cancer development has not been established, although it has been reported that uPA plays a critical role inmonocyte and macrophage chemotaxis. In this study, murine prostate cancer RM-1 cells were subcutaneously inoculated into wild-type (WT), uPA-/-, and uPAR-/- mice. Tumor volume was significantly diminished in both uPA-/- and uPAR-/- mice compared withWT controls. Greater inhibition of tumor volume was also observed in uPA-/- mice compared with uPAR-/- mice, suggesting the important contribution of stromal-derived uPA to sustain the tumor growth. Immunohistochemical staining revealed that tumors in uPA-/- and uPAR-/- mice displayed significantly lower proliferative indices, higher apoptotic indices, and less neovascularity compared with the tumors in WT mice. Tumors in uPA-/- and uPAR-/- mice displayed significantly less macrophage infiltration as demonstrated by F4/80 staining and MAC3+ cell numbers by flow cytometry compared with the tumors from WT mice. These findings suggest that the uPA/uPAR axis acts in both autocrine and paracrine manners in the tumor microenvironment, and activation of uPA/uPAR axis is essential for macrophage infiltration into prostate tumors.

Original languageEnglish (US)
Pages (from-to)23-30
Number of pages8
JournalNeoplasia
Volume13
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Fingerprint

Urokinase Plasminogen Activator Receptors
Urokinase-Type Plasminogen Activator
Plasminogen Activators
Prostatic Neoplasms
Macrophages
Tumor Microenvironment
Neoplasms
Tumor Burden
Staining and Labeling
Neoplasm Metastasis
Chemotaxis
Cell Movement
Extracellular Matrix
Prostate
Flow Cytometry
Cell Count

ASJC Scopus subject areas

  • Cancer Research

Cite this

Activation of urokinase plasminogen activator and its receptor axis is essential for macrophage infiltration in a prostate cancer mouse model. / Zhang, Jian; Sud, Sudha; Mizutani, Kosuke; Gyetko, Margaret R.; Pienta, Kenneth.

In: Neoplasia, Vol. 13, No. 1, 01.2011, p. 23-30.

Research output: Contribution to journalArticle

@article{45bc8ed36847453d9f9b1b670c7ad0fd,
title = "Activation of urokinase plasminogen activator and its receptor axis is essential for macrophage infiltration in a prostate cancer mouse model",
abstract = "Macrophages within the tumor microenvironment promote angiogenesis, extracellular matrix breakdown, and tumor cell migration, invasion, and metastasis. Activation of the urokinase plasminogen activator (uPA) and its receptor (uPAR) axis promotes prostate cancer tumorigenicity, invasion, metastasis, and survival within the tumor microenvironment. The link between macrophage infiltration and the uPA/uPAR axis in prostate cancer development has not been established, although it has been reported that uPA plays a critical role inmonocyte and macrophage chemotaxis. In this study, murine prostate cancer RM-1 cells were subcutaneously inoculated into wild-type (WT), uPA-/-, and uPAR-/- mice. Tumor volume was significantly diminished in both uPA-/- and uPAR-/- mice compared withWT controls. Greater inhibition of tumor volume was also observed in uPA-/- mice compared with uPAR-/- mice, suggesting the important contribution of stromal-derived uPA to sustain the tumor growth. Immunohistochemical staining revealed that tumors in uPA-/- and uPAR-/- mice displayed significantly lower proliferative indices, higher apoptotic indices, and less neovascularity compared with the tumors in WT mice. Tumors in uPA-/- and uPAR-/- mice displayed significantly less macrophage infiltration as demonstrated by F4/80 staining and MAC3+ cell numbers by flow cytometry compared with the tumors from WT mice. These findings suggest that the uPA/uPAR axis acts in both autocrine and paracrine manners in the tumor microenvironment, and activation of uPA/uPAR axis is essential for macrophage infiltration into prostate tumors.",
author = "Jian Zhang and Sudha Sud and Kosuke Mizutani and Gyetko, {Margaret R.} and Kenneth Pienta",
year = "2011",
month = "1",
doi = "10.1593/neo.10728",
language = "English (US)",
volume = "13",
pages = "23--30",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Activation of urokinase plasminogen activator and its receptor axis is essential for macrophage infiltration in a prostate cancer mouse model

AU - Zhang, Jian

AU - Sud, Sudha

AU - Mizutani, Kosuke

AU - Gyetko, Margaret R.

AU - Pienta, Kenneth

PY - 2011/1

Y1 - 2011/1

N2 - Macrophages within the tumor microenvironment promote angiogenesis, extracellular matrix breakdown, and tumor cell migration, invasion, and metastasis. Activation of the urokinase plasminogen activator (uPA) and its receptor (uPAR) axis promotes prostate cancer tumorigenicity, invasion, metastasis, and survival within the tumor microenvironment. The link between macrophage infiltration and the uPA/uPAR axis in prostate cancer development has not been established, although it has been reported that uPA plays a critical role inmonocyte and macrophage chemotaxis. In this study, murine prostate cancer RM-1 cells were subcutaneously inoculated into wild-type (WT), uPA-/-, and uPAR-/- mice. Tumor volume was significantly diminished in both uPA-/- and uPAR-/- mice compared withWT controls. Greater inhibition of tumor volume was also observed in uPA-/- mice compared with uPAR-/- mice, suggesting the important contribution of stromal-derived uPA to sustain the tumor growth. Immunohistochemical staining revealed that tumors in uPA-/- and uPAR-/- mice displayed significantly lower proliferative indices, higher apoptotic indices, and less neovascularity compared with the tumors in WT mice. Tumors in uPA-/- and uPAR-/- mice displayed significantly less macrophage infiltration as demonstrated by F4/80 staining and MAC3+ cell numbers by flow cytometry compared with the tumors from WT mice. These findings suggest that the uPA/uPAR axis acts in both autocrine and paracrine manners in the tumor microenvironment, and activation of uPA/uPAR axis is essential for macrophage infiltration into prostate tumors.

AB - Macrophages within the tumor microenvironment promote angiogenesis, extracellular matrix breakdown, and tumor cell migration, invasion, and metastasis. Activation of the urokinase plasminogen activator (uPA) and its receptor (uPAR) axis promotes prostate cancer tumorigenicity, invasion, metastasis, and survival within the tumor microenvironment. The link between macrophage infiltration and the uPA/uPAR axis in prostate cancer development has not been established, although it has been reported that uPA plays a critical role inmonocyte and macrophage chemotaxis. In this study, murine prostate cancer RM-1 cells were subcutaneously inoculated into wild-type (WT), uPA-/-, and uPAR-/- mice. Tumor volume was significantly diminished in both uPA-/- and uPAR-/- mice compared withWT controls. Greater inhibition of tumor volume was also observed in uPA-/- mice compared with uPAR-/- mice, suggesting the important contribution of stromal-derived uPA to sustain the tumor growth. Immunohistochemical staining revealed that tumors in uPA-/- and uPAR-/- mice displayed significantly lower proliferative indices, higher apoptotic indices, and less neovascularity compared with the tumors in WT mice. Tumors in uPA-/- and uPAR-/- mice displayed significantly less macrophage infiltration as demonstrated by F4/80 staining and MAC3+ cell numbers by flow cytometry compared with the tumors from WT mice. These findings suggest that the uPA/uPAR axis acts in both autocrine and paracrine manners in the tumor microenvironment, and activation of uPA/uPAR axis is essential for macrophage infiltration into prostate tumors.

UR - http://www.scopus.com/inward/record.url?scp=78650996236&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650996236&partnerID=8YFLogxK

U2 - 10.1593/neo.10728

DO - 10.1593/neo.10728

M3 - Article

VL - 13

SP - 23

EP - 30

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 1

ER -