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developmental processes as well as in patho-logical tissue remodeling.

In mouse models of chemically induced colon and skin carcinogenesis, Yang et al.6 report that, compared to wild-type mice, Hdc-deficient mice are more susceptible to tumor formation, with increased tumor frequency and burden, suggesting that Hdc expression is important for restricting tumorigenesis. To identify Hdc-expressing cells mediating this activity, the authors generated mice express-ing a reporter gene (EGFP) under control of the Hdc promoter. Hdc-EGFP expression emanated from a discrete population of iMCs positive for CD11b and Ly6G (a subset of the Gr-1 population) that were localized to tumor peripheries and within inflamed tissue, thus identifying iMCs as a major source of histamine and potential mediators of Hdc-dependent tumor repression. Accordingly, Hdc-deficient iMCs enhanced growth of colon carcinoma allografts, in immunodeficient mice, thus indicating that iMCs could mediate tumor promotion independently of potential T cell–suppressive activity.

Tumors do not develop in spite of their ‘host’ but rather with the combined support of normal cells that comprise the tumor stroma, including fibroblasts and other niche-defining cells, vas-cular cells and various leukocyte populations. These cells participate in a maladaptive immune response to developing neoplasms— which have been described as ‘wounds that do not heal’1—that is crucial for all stages of solid tumor devel-opment. Infiltration of tumors by subtypes of myeloid cells, including macrophages, mast cells and neutrophils, can promote tumorigen-esis through the collective ability of these cells to initiate tissue remodeling, activate angiogenic programs, regulate invasive pathways and sup-press antitumor immune responses2.

Mouse tumor models have also shown that a heterogeneous population of immature myel-oid cells (iMCs) accumulates within some tumors and at their periphery. iMCs are iden-tified by cell surface markers including CD11b and Gr-1, possess morphological features of immature monocytes or granulocytes, and are often classified as myeloid-derived suppressor cells owing to their ability to repress cytotoxic T cell responses3.

Discovered a century ago, the pleiotropic effects of the immune modulator histamine have made histamine receptor antagonists common drugs to treat various conditions, for example, the well-known antihistamines target H1 recep-tors to combat allergy, whereas H2 receptor antagonists inhibit the production of stomach acid. H2 receptor antagonists are also known to inhibit the proliferation of several human colon carcinoma cell lines and the growth of xenograft colon carcinomas and melanomas4; however, H2 receptor antagonists have had limited suc-cess in cancer clinical trials5.

In this issue of Nature Medicine, Yang et al.6 report that iMCs regulate cancer development via their synthesis of histamine. Bone marrow iMCs expressed the enzyme responsible for

production of endogenous histamine, histidine decarboxylase (HDC), which in turn promoted iMC differentiation and repression of proin-flammatory cytokine expression. Hdc-deficient mice showed increased susceptibility to chemi-cally induced colon and skin cancers, indicat-ing that histamine restricts tumor growth. As neoplastic cells epigenetically turned off Hdc expression via promoter methylation in iMCs, this study suggests exogenous histamine or histamine receptor targeting could restrict the growth of cancers that are fostered by chronic inflammatory microenvironments.

Although histamine can be acquired through ingestion, HDC is solely responsible for endog-enous generation of histamine. Hdc-deficient mice show multiple phenotypic changes consistent with those observed in mice after treatment with H1 or H2 receptor antagonists, in addition to reduced mast cell numbers, altered granulocyte recruitment after anti-genic challenge, reduced permeability of cuta-neous vessels and diminished development of angiogenic vasculature7,8, thereby indicating roles for histamine and histamine receptors in

Brian Ruffell and Lisa M. Coussens are in the

Department of Pathology and Lisa M. Coussens is

at the Helen Diller Family Comprehensive Cancer

Center, University of California–San Francisco,

San Francisco, California, USA.

e-mail: lisa.coussens@ucsf.edu

Histamine restricts cancer: nothing to sneeze atBrian Ruffell & Lisa M Coussens

Histamine produced by immature myeloid cells restricts the expression of inflammatory mediators and regulates leukocyte recruitment to sites of tissue stress. Unexpectedly, cancer susceptibility is increased in mice lacking histamine, thus revealing a previously unknown mechanism whereby immature myeloid cells contribute to cancer development (pages 87–95).

Figure 1 Proposed role for histidine decarboxylase production by immature myeloid cells in inflammation-associated carcinogenesis. Yang et al.6 show how HDC-dependent production of histamine limits expression of proinflammatory cytokines in iMCs in an autocrine or paracrine manner. IL-6 and other inflammatory cytokines (not shown) may drive expression of the RAGE ligands S100A9 and S100A8 in iMCs or other cells in the tumor microenvironment via STAT3 activation. This results in increased iMC recruitment to tumors, which in turn is associated with increased tumor vascularization. IL-6 may also directly regulate proliferation of neoplastic cells through activation of STAT3. Carcinoma cells may enhance leukocyte recruitment by reducing HDC expression through other mechanisms, such as promoter methylation and subsequent silencing of HDC.

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necessary to determine whether these cells are functionally equivalent to their mouse coun-terparts and whether they are also regulated by histamine production to assess the feasibility of histamine- based therapies in cancer.

COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.

1. Dvorak, H.F. N. Engl. J. Med. 315, 1650–1659 (1986).

2. Qian, B.Z. & Pollard, J.W. Cell 141, 39–51 (2010). 3. Gabrilovich, D.I. & Nagaraj, S. Nat. Rev. Immunol. 9,

162–174 (2009). 4. Medina, V.A. & Rivera, E.S. Br. J. Pharmacol. 161,

755–767 (2010). 5. Bolton, E., King, J. & Morris, D.L. Semin. Cancer Biol.

10, 3–10 (2000). 6. Yang, X.D. et al. Nat. Med. 17, 87–95 (2011).7. Ghosh, A.K., Hirasawa, N., Ohtsu, H., Watanabe, T. &

Ohuchi, K. J. Exp. Med. 195, 973–982 (2002). 8. Ohtsu, H. & Watanabe, T. Biochem. Biophys. Res.

Commun. 305, 443–447 (2003). 9. Cheng, P. et al. J. Exp. Med. 205, 2235–2249

(2008). 10. Grivennikov, S. et al. Cancer Cell 15, 103–113

(2009). 11. Schneider, E. et al. J. Exp. Med. 202, 387–393

(2005). 12. Brandes, L.J., Queen, G.M. & LaBella, F.S. J. Cell.

Biochem. 85, 820–824 (2002).

HDC or following epigenetic silencing of the Hdc promoter6, increased IL-6 expres-sion could be a mechanism whereby iMCs enhance inflammation-dependent carcino-genesis (Fig. 1). These results identify new mechanisms through which iMCs contribute to tumor development, in addition to their established immune-suppressive3 and proan-giogenic2 capabilities.

Although H1 and H2 receptors were impor-tant for histamine-dependent maturation of iMCs, it is unclear whether these receptors also directly regulate gene expression of proinflam-matory cytokines. Intriguingly, intracellular uptake of histamine by mouse basophils via organic cation transporter-3 (OCT3) limits expression of cytokines, including IL-6, independently of conventional histamine receptors11 and instead may involve binding of cytochrome P450 enzymes12. The clinical translation of these findings requires identifica-tion of pathways by which histamine regulates iMC maturation and bioactivity. Furthermore, although there is increasing evidence that iMCs accumulate in people with cancer3, it will be

How is tumor development regulated by HDC-producing iMCs? Hdc-deficient iMCs expressed higher amounts of interleukin-6 (IL-6), and this was accompanied by increased IL-6 expression in both colon and skin tumors. IL-6 signaling induces activation of signal transducer and activator of transcription-3 (STAT3), a transcriptional inducer of the receptor for advanced glycation end products (RAGE) ligands S100A8 and S100A9. Both these RAGE ligands are expressed by iMCs9 and are important chemoattractants for iMCs3. Consistent with this, Hdc-deficient mice showed increased tissue expression of S100A8 and S100A9, and adoptive transfer of Hdc-deficient bone marrow iMCs into mice harboring allograft tumors resulted in an approximately two- to threefold increase in iMC recruitment.

IL-6–dependent activation of STAT3 is also an important mediator of colon car-cinogenesis through regulation of neoplastic cell survival10 and, in the allograft model, IL-6–deficient iMCs were unable to pro-mote tumor growth. Thus, in the absence of

receptor TIE2 or the related protein TIE1 and remain orphan ligands4. ANGPTL4 is known mostly for its role in the regulation of plasma triglyceride concentrations5. As hyper-triglyceridemia is a characteristic of the nephrotic syndrome seen in MCD, and angiogenesis- related genes have previously been shown to be regulated in response to glomerular injury6, Clement et al.3 investigated the role of ANGPTL4 in MCD. The authors used a transgenic approach to show that podocyte- specific overexpression of Angptl4 (NPHS2-Angptl4) in rats leads to large-scale albuminuria, loss of glomerular basement membrane (GBM) charge and fusion of podocyte foot pro cess es (effacement)3.

Notably, the expression of Angptl4 was reduced after glucocorticoid treatment, which is consistent with the glucocorticoid sensitivity of human MCD. In contrast, in a rat model with adipose tissue–specific overexpression of Angptl4 (aP2-Angptl4), the authors observed increased circulating concentrations of ANGPTL4, but no

Since 1905, when Friedrich Muller first used the term ‘nephrosis’1, clinicians and patholo-gists have attempted to separate the unusual condition of ‘lipoid nephrosis’2, now more commonly referred to as minimal change dis-ease (MCD), from the main nephropathies. This reversible disease is clinically charac-terized by its often lengthy course, edema, marked albuminuria and the absence of hypertension, cardiac hypertrophy and renal insufficiency. The ‘minimal changes’ in MCD refer to ultrastructural alterations of special-ized kidney epithelial cells called podocytes. In MCD, the podocyte foot processes, which are individual cellular extensions that regulate kidney filter permselectivity, are fused. Since the discovery of MCD, two main questions have occupied researchers: what causes MCD

and, in contrast to other proteinuric kidney diseases, why doesn’t MCD progress to renal insufficiency?

In this issue of Nature Medicine, a study by Clement et al.3 provides some answers to the first question by introducing a molecular mediator of human MCD: the secreted glyco-protein angiopoietin-like-4 (ANGPTL4). In podocytes from experimental rodent models of nephrotic syndrome and human MCD, ANGPTL4 expression is upregulated, resulting in the secretion of hyposialylated ANGPTL4 into the glomerular capillary wall and protei-nuria in MCD rats. Feeding these rats a sialic acid precursor increases ANGPTL4 sialyla-tion and reduces albuminuria. Treatment of MCD with sialic acid precursors may there-fore be a viable therapeutic strategy to reduce the symptoms of nephrotic syndrome.

ANGPTL4 belongs to a group of proteins that are structurally similar to the angiogenesis- regulating factors angiopoietins, but angiopoietin- like proteins do not bind the angiopoietin

Jochen Reiser is in the Department of Medicine,

University of Miami Miller School of Medicine,

Miami, Florida, USA.

e-mail: jreiser@med.miami.edu

Filtering new facts about kidney diseaseJochen Reiser

Loss of kidney filter function during nephrotic syndrome results in loss of protein from the blood into the urine (proteinuria). A new study mechanistically links proteinuria to dysregulated expression and post-transcriptional modification of the secreted glycoprotein angiopoietin-like-4 in kidney glomerular podocytes (pages 117–122).

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