Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma

Takahiro Tsujikawa, Tomonori Yaguchi, Gaku Ohmura, Shigeki Ota, Asuka Kobayashi, Naoshi Kawamura, Tomonobu Fujita, Hiroshi Nakano, Taketoshi Shimada, Takeshi Takahashi, Ryuta Nakao, Akio Yanagisawa, Yasuo Hisa, Yutaka Kawakami

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4- cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2-like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2-like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4 - cells, metastasized to lymph nodes which contained CCL22 producing M2-like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2-like macrophage-dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.

Original languageEnglish
Pages (from-to)2755-2766
Number of pages12
JournalInternational Journal of Cancer
Volume132
Issue number12
DOIs
Publication statusPublished - 2013 Jun 15

Fingerprint

Lymph Nodes
Macrophages
Neoplasm Metastasis
Neoplasms
Tongue Neoplasms
Carcinoma, squamous cell of head and neck
Cell Line
Tumor Microenvironment
Cell Movement
Ligands

Keywords

  • CCL22
  • CCR4
  • head and neck cancer
  • lymph node metastasis
  • macrophage

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma. / Tsujikawa, Takahiro; Yaguchi, Tomonori; Ohmura, Gaku; Ota, Shigeki; Kobayashi, Asuka; Kawamura, Naoshi; Fujita, Tomonobu; Nakano, Hiroshi; Shimada, Taketoshi; Takahashi, Takeshi; Nakao, Ryuta; Yanagisawa, Akio; Hisa, Yasuo; Kawakami, Yutaka.

In: International Journal of Cancer, Vol. 132, No. 12, 15.06.2013, p. 2755-2766.

Research output: Contribution to journalArticle

Tsujikawa, T, Yaguchi, T, Ohmura, G, Ota, S, Kobayashi, A, Kawamura, N, Fujita, T, Nakano, H, Shimada, T, Takahashi, T, Nakao, R, Yanagisawa, A, Hisa, Y & Kawakami, Y 2013, 'Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma', International Journal of Cancer, vol. 132, no. 12, pp. 2755-2766. https://doi.org/10.1002/ijc.27966
Tsujikawa, Takahiro ; Yaguchi, Tomonori ; Ohmura, Gaku ; Ota, Shigeki ; Kobayashi, Asuka ; Kawamura, Naoshi ; Fujita, Tomonobu ; Nakano, Hiroshi ; Shimada, Taketoshi ; Takahashi, Takeshi ; Nakao, Ryuta ; Yanagisawa, Akio ; Hisa, Yasuo ; Kawakami, Yutaka. / Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma. In: International Journal of Cancer. 2013 ; Vol. 132, No. 12. pp. 2755-2766.
@article{86dcbabe950146f98b1d8b83169fda04,
title = "Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma",
abstract = "Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5{\%}) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4- cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4{\%} of tongue cancer tissues) or CD206+ M2-like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2-like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4 - cells, metastasized to lymph nodes which contained CCL22 producing M2-like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2-like macrophage-dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.",
keywords = "CCL22, CCR4, head and neck cancer, lymph node metastasis, macrophage",
author = "Takahiro Tsujikawa and Tomonori Yaguchi and Gaku Ohmura and Shigeki Ota and Asuka Kobayashi and Naoshi Kawamura and Tomonobu Fujita and Hiroshi Nakano and Taketoshi Shimada and Takeshi Takahashi and Ryuta Nakao and Akio Yanagisawa and Yasuo Hisa and Yutaka Kawakami",
year = "2013",
month = "6",
day = "15",
doi = "10.1002/ijc.27966",
language = "English",
volume = "132",
pages = "2755--2766",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "12",

}

TY - JOUR

T1 - Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma

AU - Tsujikawa, Takahiro

AU - Yaguchi, Tomonori

AU - Ohmura, Gaku

AU - Ota, Shigeki

AU - Kobayashi, Asuka

AU - Kawamura, Naoshi

AU - Fujita, Tomonobu

AU - Nakano, Hiroshi

AU - Shimada, Taketoshi

AU - Takahashi, Takeshi

AU - Nakao, Ryuta

AU - Yanagisawa, Akio

AU - Hisa, Yasuo

AU - Kawakami, Yutaka

PY - 2013/6/15

Y1 - 2013/6/15

N2 - Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4- cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2-like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2-like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4 - cells, metastasized to lymph nodes which contained CCL22 producing M2-like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2-like macrophage-dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.

AB - Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4- cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2-like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2-like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4 - cells, metastasized to lymph nodes which contained CCL22 producing M2-like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2-like macrophage-dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.

KW - CCL22

KW - CCR4

KW - head and neck cancer

KW - lymph node metastasis

KW - macrophage

UR - http://www.scopus.com/inward/record.url?scp=84876124085&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876124085&partnerID=8YFLogxK

U2 - 10.1002/ijc.27966

DO - 10.1002/ijc.27966

M3 - Article

C2 - 23180648

AN - SCOPUS:84876124085

VL - 132

SP - 2755

EP - 2766

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 12

ER -