Bimodal role of Kupffer cells during colorectal cancer liver metastasis

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3+ T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of protumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.

Original languageEnglish
Pages (from-to)606-613
Number of pages8
JournalCancer Biology and Therapy
Volume14
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Keywords

  • Colorectal cancer
  • Kupffer cell
  • Liver metastases
  • Macrophage
  • Tumor-associated macrophages

Cite this

@article{a01e5745bf454bc7b1d6acde8fee8b6f,
title = "Bimodal role of Kupffer cells during colorectal cancer liver metastasis",
abstract = "Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3+ T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of protumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.",
keywords = "Colorectal cancer, Kupffer cell, Liver metastases, Macrophage, Tumor-associated macrophages",
author = "Wen, {Shu Wen} and Ager, {Eleanor I.} and Christopher Christophi",
year = "2013",
month = "7",
doi = "10.4161/cbt.24593",
language = "English",
volume = "14",
pages = "606--613",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Taylor & Francis",
number = "7",

}

Bimodal role of Kupffer cells during colorectal cancer liver metastasis. / Wen, Shu Wen; Ager, Eleanor I.; Christophi, Christopher.

In: Cancer Biology and Therapy, Vol. 14, No. 7, 07.2013, p. 606-613.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Bimodal role of Kupffer cells during colorectal cancer liver metastasis

AU - Wen, Shu Wen

AU - Ager, Eleanor I.

AU - Christophi, Christopher

PY - 2013/7

Y1 - 2013/7

N2 - Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3+ T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of protumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.

AB - Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3+ T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of protumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.

KW - Colorectal cancer

KW - Kupffer cell

KW - Liver metastases

KW - Macrophage

KW - Tumor-associated macrophages

UR - http://www.scopus.com/inward/record.url?scp=84881138569&partnerID=8YFLogxK

U2 - 10.4161/cbt.24593

DO - 10.4161/cbt.24593

M3 - Article

VL - 14

SP - 606

EP - 613

JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

SN - 1538-4047

IS - 7

ER -