Infiltration of Neutrophils Is Required for Acquisition of Metastatic Phenotype of Benign Murine Fibrosarcoma Cells: Implication of Inflammation-Associated Carcinogenesis and Tumor Progression

Hiroshi Tazawa, Futoshi Okada, Tokushige Kobayashi, Mitsuhiro Tada, Yukiko Mori, Yoshie Une, Fujiro Sendo, Masanobu Kobayashi, Masuo Hosokawa

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin β2 knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2′-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

Original languageEnglish
Pages (from-to)2221-2232
Number of pages12
JournalAmerican Journal of Pathology
Volume163
Issue number6
Publication statusPublished - Dec 2003
Externally publishedYes

Fingerprint

Neutrophil Infiltration
Fibrosarcoma
Carcinogenesis
Inflammation
Phenotype
Porifera
Gelatin
Neutrophils
Neoplasms
Tumor Cell Line
Knockout Mice
Blood Circulation
Foreign Bodies
Inbred C57BL Mouse
Growth and Development
Granulocytes
Nude Mice
Integrins
Anti-Idiotypic Antibodies
Clone Cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Infiltration of Neutrophils Is Required for Acquisition of Metastatic Phenotype of Benign Murine Fibrosarcoma Cells : Implication of Inflammation-Associated Carcinogenesis and Tumor Progression. / Tazawa, Hiroshi; Okada, Futoshi; Kobayashi, Tokushige; Tada, Mitsuhiro; Mori, Yukiko; Une, Yoshie; Sendo, Fujiro; Kobayashi, Masanobu; Hosokawa, Masuo.

In: American Journal of Pathology, Vol. 163, No. 6, 12.2003, p. 2221-2232.

Research output: Contribution to journalArticle

Tazawa, Hiroshi ; Okada, Futoshi ; Kobayashi, Tokushige ; Tada, Mitsuhiro ; Mori, Yukiko ; Une, Yoshie ; Sendo, Fujiro ; Kobayashi, Masanobu ; Hosokawa, Masuo. / Infiltration of Neutrophils Is Required for Acquisition of Metastatic Phenotype of Benign Murine Fibrosarcoma Cells : Implication of Inflammation-Associated Carcinogenesis and Tumor Progression. In: American Journal of Pathology. 2003 ; Vol. 163, No. 6. pp. 2221-2232.
@article{db4318840fac40c286f16903bd6edd34,
title = "Infiltration of Neutrophils Is Required for Acquisition of Metastatic Phenotype of Benign Murine Fibrosarcoma Cells: Implication of Inflammation-Associated Carcinogenesis and Tumor Progression",
abstract = "QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin β2 knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2′-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.",
author = "Hiroshi Tazawa and Futoshi Okada and Tokushige Kobayashi and Mitsuhiro Tada and Yukiko Mori and Yoshie Une and Fujiro Sendo and Masanobu Kobayashi and Masuo Hosokawa",
year = "2003",
month = "12",
language = "English",
volume = "163",
pages = "2221--2232",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Infiltration of Neutrophils Is Required for Acquisition of Metastatic Phenotype of Benign Murine Fibrosarcoma Cells

T2 - Implication of Inflammation-Associated Carcinogenesis and Tumor Progression

AU - Tazawa, Hiroshi

AU - Okada, Futoshi

AU - Kobayashi, Tokushige

AU - Tada, Mitsuhiro

AU - Mori, Yukiko

AU - Une, Yoshie

AU - Sendo, Fujiro

AU - Kobayashi, Masanobu

AU - Hosokawa, Masuo

PY - 2003/12

Y1 - 2003/12

N2 - QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin β2 knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2′-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

AB - QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin β2 knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2′-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

UR - http://www.scopus.com/inward/record.url?scp=0345707663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0345707663&partnerID=8YFLogxK

M3 - Article

C2 - 14633597

AN - SCOPUS:0345707663

VL - 163

SP - 2221

EP - 2232

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -