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Trabectedin: A drug from the sea that strikes tumor-associated macrophages.

Allavena P, Germano G, Belgiovine C, D'Incalci M, Mantovani A - Oncoimmunology (2013)

Bottom Line: Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis.We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes).The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Clinical and Research Institute Humanitas; Rozzano, Milan, Italy.

ABSTRACT
Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis. We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes). The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Mechanisms of action of trabectedin. The marine anticancer agent trabectedin is cytotoxic for tumor-associated macrophages (TAMs) and neoplastic cells. By inhibiting the production of the chemokine CCL2 trabectedin also decreases monocyte recruitment in tumors. The effects of trabectedin on the tumor microenvironment are important for its antitumor activity.
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Figure 1: Figure 1. Mechanisms of action of trabectedin. The marine anticancer agent trabectedin is cytotoxic for tumor-associated macrophages (TAMs) and neoplastic cells. By inhibiting the production of the chemokine CCL2 trabectedin also decreases monocyte recruitment in tumors. The effects of trabectedin on the tumor microenvironment are important for its antitumor activity.

Mentions: The real issue was to investigate whether trabectedin would be able to kill mononuclear phagocytes in vivo and in the context of cancer. In different mouse tumor models, trabectedin significantly decreased the number of circulating monocytes as well as that of splenic macrophages and TAMs, but had no effect on neutrophils and lymphocytes. To prove that the cytotoxic activity of trabectedin on mononuclear phagocytes is relevant for its antitumor activity, we took advantage of a trabectedin-resistant tumor cell line. Mice bearing trabectedin-resistant tumors were indeed normally sensitive to the antitumor activity of trabectedin, in spite of the fact that the same cancer cells exhibited a pronounced resistance against the drug in vitro.10 We therefore hypothesized that trabectedin exerts major inhibitory effects on TAMs. In line with this interpretation, the adoptive transfer of macrophages to trabectedin-treated mice significantly reinstated tumor growth. Thus, the targeting of macrophages in vivo is a key component of the antitumor activity of trabectedin. Nevertheless, effects other than macrophage depletion may also contribute to the pronounced antineoplastic potential of this drug. Immunohistochemical studies on tumor sections revealed indeed that trabectedin significantly reduces the expression levels of the angiogenic mediator vascular endothelial growth factor (VEGF) and the chemokine CCL2 in tumor vessels.10 Thus, besides direct killing mononuclear phagocytes, trabectedin may limit the recruitment of circulating monocytes into neoplastic lesions and inhibit angiogenesis (Fig. 1).


Trabectedin: A drug from the sea that strikes tumor-associated macrophages.

Allavena P, Germano G, Belgiovine C, D'Incalci M, Mantovani A - Oncoimmunology (2013)

Figure 1. Mechanisms of action of trabectedin. The marine anticancer agent trabectedin is cytotoxic for tumor-associated macrophages (TAMs) and neoplastic cells. By inhibiting the production of the chemokine CCL2 trabectedin also decreases monocyte recruitment in tumors. The effects of trabectedin on the tumor microenvironment are important for its antitumor activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716756&req=5

Figure 1: Figure 1. Mechanisms of action of trabectedin. The marine anticancer agent trabectedin is cytotoxic for tumor-associated macrophages (TAMs) and neoplastic cells. By inhibiting the production of the chemokine CCL2 trabectedin also decreases monocyte recruitment in tumors. The effects of trabectedin on the tumor microenvironment are important for its antitumor activity.
Mentions: The real issue was to investigate whether trabectedin would be able to kill mononuclear phagocytes in vivo and in the context of cancer. In different mouse tumor models, trabectedin significantly decreased the number of circulating monocytes as well as that of splenic macrophages and TAMs, but had no effect on neutrophils and lymphocytes. To prove that the cytotoxic activity of trabectedin on mononuclear phagocytes is relevant for its antitumor activity, we took advantage of a trabectedin-resistant tumor cell line. Mice bearing trabectedin-resistant tumors were indeed normally sensitive to the antitumor activity of trabectedin, in spite of the fact that the same cancer cells exhibited a pronounced resistance against the drug in vitro.10 We therefore hypothesized that trabectedin exerts major inhibitory effects on TAMs. In line with this interpretation, the adoptive transfer of macrophages to trabectedin-treated mice significantly reinstated tumor growth. Thus, the targeting of macrophages in vivo is a key component of the antitumor activity of trabectedin. Nevertheless, effects other than macrophage depletion may also contribute to the pronounced antineoplastic potential of this drug. Immunohistochemical studies on tumor sections revealed indeed that trabectedin significantly reduces the expression levels of the angiogenic mediator vascular endothelial growth factor (VEGF) and the chemokine CCL2 in tumor vessels.10 Thus, besides direct killing mononuclear phagocytes, trabectedin may limit the recruitment of circulating monocytes into neoplastic lesions and inhibit angiogenesis (Fig. 1).

Bottom Line: Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis.We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes).The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Clinical and Research Institute Humanitas; Rozzano, Milan, Italy.

ABSTRACT
Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis. We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes). The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.

No MeSH data available.


Related in: MedlinePlus