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A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis
Published on: October 24, 2015
Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4
Takuto Nosaka1,2, Tomohisa Baba3, Yamato Tanabe1,4
1Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Abstract:
Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB4, augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB4.
Insights
Alveolar macrophages (AMs) promote lung metastasis by producing leukotriene B4 (LTB4), a key growth factor. Interstitial macrophages (IMs) recruit AMs to the lungs, driving hepatocellular carcinoma (HCC) progression.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Lung macrophages comprise alveolar macrophages (AMs) and interstitial macrophages (IMs), with IMs implicated in lung metastasis.
- The specific role of AMs in lung metastasis has remained largely unclear.
- Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality worldwide, with lung metastasis being a common complication.
Purpose of the Study:
- To elucidate the role of alveolar macrophages (AMs) in hepatocellular carcinoma (HCC) lung metastasis.
- To investigate the mechanisms by which AMs contribute to tumor growth and metastasis in the lungs.
- To identify potential therapeutic targets for preventing or treating HCC lung metastasis.
Main Methods:
- Establishment of a mouse model of HCC lung metastasis via intravenous injection of BNL cells.
- Comprehensive analysis of arachidonic acid metabolite levels, including leukotrienes and prostaglandins (PGs).
- Pharmacological inhibition of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) pathways.
- In vitro assessment of LTB4's effect on HCC cell proliferation.
- Selective depletion of AMs using clodronate liposomes.
- Immunohistochemical analysis of 5-LOX expression in human HCC patient lung tissues.
- Investigation of chemokine (CCL2) and receptor (CCR2) involvement in macrophage recruitment.
Main Results:
- HCC metastasis induced infiltration of both AMs and IMs, alongside increased leukotrienes and PGs in the lungs.
- Inhibition of 5-LOX, but not COX, significantly reduced metastatic foci, especially larger ones.
- Leukotriene B4 (LTB4) enhanced HCC cell proliferation in vitro.
- AMs demonstrated higher 5-LOX and LTB4 expression than IMs during metastasis, a finding consistent in human HCC patients.
- Selective AM depletion reduced LTB4 levels and metastatic burden.
- Interstitial macrophages (IMs) produced CCL2, recruiting CCR2-expressing AMs to the metastatic lungs.
Conclusions:
- Alveolar macrophages (AMs) play a critical role in promoting HCC lung metastasis.
- AMs contribute to metastasis by producing LTB4, which enhances tumor cell proliferation.
- IMs facilitate AM recruitment to the lungs via CCL2 signaling, creating a pro-metastatic microenvironment.
- Targeting the 5-LOX pathway and AM recruitment presents a potential therapeutic strategy for HCC lung metastasis.
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