Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4

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, LTB, 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 LTB 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 LTB 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, LTB.

Tumor Microenvironment Modulates Immunological Outcomes of Myeloid Cells with mTORC1 Disruption

“…The lung microenvironment comprises airway, AM, and IM, as well as inflammatory and patrolling monocytes. Previous studies have shown that patrolling monocytes can control tumor metastasis to the lungs (28), whereas AM contribute to the promotion of lung metastasis by suppressing Th1 response (30,42). However, we did not observe the causal relationship of AM in the experimental LLC lung metastasis model.…”

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

“…These observations would indicate that bone marrow contains AM precursors, which can migrate through circulating blood into lung to differentiate into mature AMs. Likewise, we observed in a mouse lung metastasis model that blood-derived AM precursors can infiltrate into lungs to differentiate into AMs [39], as discussed in the following section. However, it remains elusive on the precise phenotypes of AM precursors in bone marrow and circulating blood.…”

“…We recently observed that an intravenous injection of mouse hepatocellular carcinoma cells caused lung metastasis, together with increases in both F4/80 + CD11b − CD11c + AMs and F4/80 + CD11b + CD11c − IMs [39]. Intratracheal injection of CLL transiently reduced AMs but not IMs, and attenuated lung metastasis upon its administration at a later step when tumor cells had already seeded into lungs.…”

“…Intratracheal injection of CLL transiently reduced AMs but not IMs, and attenuated lung metastasis upon its administration at a later step when tumor cells had already seeded into lungs. In this metastatic model, AMs increased independently of cell proliferation while blood-borne CCR2-expressing AM precursors migrated from circulation into lungs by the action of CCL2 produced by IMs [39]. Migrated AM precursors matured to express F4/80 and CD11c, but not CD11b, the marker which is distinct for MAMs [16].…”

The innate immune architecture of lung tumors and its implication in disease progression

“…AMΦ and other innate immune cells can also prepare the lungs for metastatic seeding through means of immune stimulation. In mouse models of hepatocellular carcinoma, AMΦ‐derived leukotriene B 4 has been shown to increase metastatic permissiveness of the lungs, such that inhibition of the leukotriene‐generating enzyme, 5‐lipoxygenase (Alox5), is sufficient to prevent pulmonary colonization (Figure A). Neutrophils also contribute to Alox5 production in breast cancer models, which facilitates the production of leukotrienes , suggesting that these mechanisms may be more universally applicable to lung metastases from multiple primary sources.…”