In the last 5 years, global gene expression profiling has allowed for the subclassification of the heterogeneous disease of breast cancer into new subgroups with prognostic significance. However, for most subgroups, the nature of the contributions of individual genes to the clinical phenotypes remains largely unknown. In this issue of the JCI, Moyano and colleagues further examine the oncogenic potential of the small heat shock protein α-basic–crystallin, commonly expressed in tumors of the basal-like breast cancer subtype associated with poor prognosis, and show that it is an oncogenic protein in the breast.
Sofia K. Gruvberger Saal , Ramon Parsons
The low molecular weight region of the serum peptidome contains protein fragments derived from 2 sources: (a) high-abundance endogenous circulating proteins and (b) cell and tissue proteins. While some researchers have dismissed the serum peptidome as biological trash, recent work using mass spectrometry–based (MS-based) profiling has indicated that the peptidome may reflect biological events and contain diagnostic biomarkers. In this issue of the JCI, Villanueva et al. report on MS-based peptide profiling of serum samples from patients with advanced prostate, bladder, or breast cancer as well as from healthy controls. Surprisingly, the peptides identified as cancer-type–specific markers proved to be products of enzymatic breakdown generated after patient blood collection. The impact of these results on cancer biomarker discovery efforts is significant because it is widely believed that proteolysis occurring ex vivo should be suppressed because it destroys endogenous biomarkers. Villanueva et al. now suggest that this suppression may in fact be preventing biomarker generation.
Lance A. Liotta, Emanuel F. Petricoin
Gastric mucosa-associated lymphoid tissue (MALT) lymphomas can arise in a variety of extranodal sites. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations, all affecting the NF-κB pathway, have been implicated in the development and progression of MALT lymphoma. The most common is the translocation t(11;18)(q21;q21), which results in a fusion of the cIAP2 region on chromosome 11q21 with the MALT1 gene on chromosome 18q21 and is present in more than one-third of cases. The frequency of this translocation is site-related: common in the gastrointestinal tract and lung, rare in conjunctiva and orbit, and almost absent in salivary glands, thyroid, liver, and skin. In this issue of the JCI, Hu et al. add to our understanding of the molecular consequences of this translocation, showing that its fusion product, cIAP2-MALT1, may concomitantly contribute to lymphomagenesis both as a tumor suppressor gene and as an oncogene.
Francesco Bertoni, Emanuele Zucca
Hair follicle stem cells sustain growth and cycling of the hair follicle and are located in the permanent portion of the follicle known as the bulge. In this issue of the JCI, Ohyama et al. report the characterization of global gene expression patterns of human hair follicle stem cells after their isolation using sophisticated laser capture techniques to microdissect out bulge cells. They discovered a panel of cell surface markers useful for isolating living hair follicle stem cells, a finding with potential therapeutic implications since isolated stem cells in mice can generate new hair follicles when transplanted to other mice. The findings of Ohyama et al. validate the use of the mouse for studying hair follicle biology but also underscore critical differences between mouse and human stem cell markers. In particular, CD34, which delineates hair follicle stem cells in the mouse, is not expressed by human hair follicle stem cells, while CD200 is expressed by stem cells in both species. Ultimately, this information will assist efforts to develop cell-based and cell-targeted treatments for skin disease.
George Cotsarelis
Ghrelin, produced in the stomach, acts on growth hormone secretagogue receptors (GHSRs) in hypothalamic neurons to potently increase food intake. However, male mice with deletions of ghrelin (Ghrl–/– mice) or GHSR (Ghsr–/– mice) display normal growth and regulation of food intake. Furthermore, adult Ghrl–/– mice display a normal sensitivity to high-fat diet–induced obesity. These findings from early studies raised the question as to whether the ghrelin system is an essential component for the regulation of food intake and body weight homeostasis. However, recent studies by Wortley et al. and Zigman et al. demonstrate that Ghrl–/– and Ghsr–/– mice are resistant to diet-induced obesity when fed a high-fat diet during the early post-weaning period. This commentary highlights 3 key issues raised by these 2 reports: (a) the impact of ghrelin on the development of metabolic systems; (b) the constitutive activity of GHSR; and (c) gender differences in the sensitivity to deletion of the ghrelin signaling system.
Kevin L. Grove, Michael A. Cowley
Minor histocompatibility antigens (mHAgs) selectively expressed by cells or cell subsets of the hematopoietic system are targets of the T cell–mediated graft-versus-leukemia response that develops following allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies. This observation has served as the rationale for utilizing mHAg-specific immunotherapy for the treatment of particular patients. However, at present, only a select and small number of patients could potentially benefit from mHAg-based immunotherapy. A report from de Rijke et al. in this issue of the JCI describes a new hematopoietic lineage–specific HLA-B7–restricted mHAg associated with remission of chronic myeloid leukemia. This result represents another example of an mHAg-mediated graft-versus-leukemia response, thereby expanding the number of patients eligible for mHAg-based immunotherapy in the setting of HSCT.
Eric Spierings, Els Goulmy
The recent discovery of the Gi protein–coupled receptor GPR109A (HM74A in humans; PUMA-G in mice) as a receptor for nicotinic acid has provided the opportunity to gain greater understanding of the underlying biology contributing to the clinical efficacy (increases in HDL, decreases in VLDL, LDL, and triglycerides) and the characteristic side-effect profile of nicotinic acid. GPR109A has been proven to be the molecular target for the actions of nicotinic acid on adipose tissue, and in this issue of the JCI, Benyó et al. have confirmed the involvement of GPR109A in the nicotinic acid–induced flushing response, a common side effect. The involvement of GPR109A in both the desirable and undesirable clinical actions of nicotinic acid raises interesting questions regarding the function of this receptor.
Nicholas B. Pike
A life-saving response to hypoglycemia requires rapid sensing of decreases in glycemia and consequent brisk glucagon secretion. Preceding studies have shown that mice lacking glucose transporter type 2 (GLUT2) lose this response. In this issue of the JCI, Marty et al. report that glucose sensing and consequent pancreatic glucagon secretion are restored by re-expression of GLUT2 in glial but not neuronal cells. A new, glucose-sensing role is ascribed to GLUT2-expressing glial cells.
Amira Klip, Meredith Hawkins
Glucagon-like peptide–1 (GLP-1) has a diverse set of peripheral actions which all serve to promote enhanced glucose tolerance, and for this reason it has become the basis for new treatments for type 2 diabetes. In this issue of the JCI, Knauf et al. provide clear evidence that GLP-1 signaling in the CNS is also linked to the control of peripheral glucose homeostasis by inhibiting non–insulin-mediated glucose uptake by muscle and increasing insulin secretion from the pancreas. The authors’ work points to an important need to integrate diverse GLP-1 signaling actions and peripheral GLP-1 function in order to better understand both normal and abnormal glucose homeostasis.
David A. D’Alessio, Darleen A. Sandoval, Randy J. Seeley
Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts. Overexpression and deposition of ECM components are dominant features of fibrotic diseases, including hepatic fibrosis. The contribution of CD4+ Th2 cells to hepatic fibrosis has been well described. Now, in this issue of the JCI, Novobrantseva et al. provide data to suggest that hepatic B cells also play a role in liver injury. In a carbon tetrachloride–induced mouse model of hepatic fibrosis, T cell–deficient mice developed severe liver fibrosis; however, in B cell–deficient animals, hepatic fibrosis was attenuated. This study provides new insight into our understanding of the cells involved in mediating the adaptive immune response that leads to hepatic fibrosis.
Rashpal K. Bhogal, Constantin A. Bona
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