The maintenance of heme homeostasis, mucosa cell renewal and redox environment in the intestine is essential to permit digestion, absorption, cell proliferation, cell apoptosis, immune response and to avoid the development of gut disorders. The Feline Leukemia Virus, subgroup C, Receptor 1a (FLVCR1a) is a heme exporter with an established role in erythroid cells, macrophages and hepatocytes. Flvcr1a is expressed in almost all cell types including intestinal cells, suggesting a role for this protein also in this tissue. In a recent paper published on Antioxidants and Redox Signaling, Fiorito et al. describe the role of FLVCR1a in the intestine taking advantage of intestine specific conditional Flvcr1a−knockout mice and of Flvcr1a−depleted colon adenocarcinoma Caco2 cells. The authors show that FLVCR1a−mediated heme export does not contribute to dietary heme absorption processes and that FLVCR1a is involved in the export of the excess of de novo synthesized heme from intestinal cells. In addition, they show that FLVCR1a participates in intestinal cell proliferation and in the maintenance of the peculiar homeostasis of proliferating cells, including their redox status and metabolic activity. Thanks to these functions, FLVCR1a is crucial for the survival of mice in a model of ulcerative colitis. The present work represents the first description of the function of the heme exporter FLVCR1a in the intestine and an advance in the understanding of heme metabolism in this tissue. The findings shed light on the role of heme export in heme absorption processes and unravel a new role for heme export in the control of mucosal renewal and in proliferating cell redox status and metabolic activity, demonstrating for the first time a crucial role for FLVCR1a in maintaining intestinal homeostasis in both physiologic and pathologic conditions.
A paper in collaboration between the group of Federica Cavallo and the group of Emanuela Noris (Institute for Sustainable Plant Protection, CNR, Torino, Italy) show that the rat ErbB2 tyrosine kinase receptor produced in plants is immunogenic in mice and confers protective immunity against ErbB2+ mammary cancer.
Overexpression and mutations of ErbB proteins lead to several malignancies including breast, lung, pancreatic, bladder and ovary carcinomas. ErbB2 is immunogenic and is an ideal candidate for cancer immunotherapy. In this paper (http://onlinelibrary.wiley.com/doi/10.1111/pbi.12367/epdf), we investigated the possibility of expressing the extracellular (EC) domain of rErbB2 in Nicotiana benthamiana plants. Synthetic variants of the rErbB2 gene portion encoding the EC domain, optimized with a human codon usage and either linked to the full TM domain, to a portion of it, or deprived of it were cloned in the pEAQ-HT expression vector as 6X His tag fusions and used to infiltrate Nicotiana benthamiana leaves. All rErbB2 variants were transiently expressed, but that expressing the EC domain without TM was the most expressed protein. When crude soluble extracts expressing this rErbB2 variant were administered to BALB/c mice, specific rErbB2 immune responses were triggered. Moreover, a potent antitumour activity was induced when vaccinated mice were challenged with syngeneic transplantable rErbB2+ mammary carcinoma cells.
Feline Leukemia Virus subgroup C Receptor 1 (Flvcr1) gene encodes for two heme exporters, FLVCR1a and FLVCR1b localized at the plasma and mitochondrial membrane, respectively. In a recent paper published on Haematologica, Sonia Mercurio and collegues addressed the specific functions of Flvcr1a and Flvcr1b in erythropoiesis, the process that produces the highest amount of heme. They showed that, in mice and zebrafish, Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while Flvcr1b contributes to the expansion phase and it is required for differentiation. Moreover, by using FLVCR1a- or FLVCR1a/1b-down-regulated K562 cells, they established a link, on one hand, between FLVCR1a deficiency, cytosolic heme accumulation and defective proliferation, and, on the other, between FLVCR1a/1b-down-regulation, mitochondrial heme accumulation and impairment of both proliferation and differentiation. These data support a model in which the coordinated expression of Flvcr1a and Flvcr1b contributes to control the size of the cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobin production during their terminal maturation. The studies on Flvcr1a and Flvcr1b, not only in erythroid cells but also in other cell types like hepatocytes and intestinal cells, reveal the exquisite mechanisms in controlling heme balance within the cell. Future work is needed to elucidate how intracellular heme transport coordinates with heme synthesis and degradation to achieve optimal intracellular heme balance.
Neonatal cancer is an issue of real urgency in oncology. Of the various therapeutic strategies used against this category of malignancy, immune-based therapies are the most promising, however the prevention of pediatric cancer has not yet become a reality. In this study, published on OncoImmunology, Giuseppina Barutello and coworkers applied a DNA vaccination strategy against Her2/neu (neu) in the framework of the pre-birth immunization in order to gauge whether maternal immunization can be used in neonatal cancer immune-prevention. Exploiting the BALB-neuT mouse model of autochthonous mammary carcinogenesis, the authors observed a significantly extended tumor-free and overall survival in BALB-neuT offspring born and fed by mothers vaccinated against neu, as compared to controls. Maternally derived anti-neu IgG were successfully transferred from mothers to newborns and were responsible for the protective effect. The vaccinated-mother’s offspring also developed an active immunity against neu as revealed by the presence of T-cell-mediated cytotoxicity against the neu immunodominant peptide. This active response was due to the milk transfer of immune-complexes formed between the neu extracellular domain, shed from vaccine-transfected muscle cells, and the anti-neu IgG induced by the vaccine. These findings show that maternal immunization has the potential to hamper mammary carcinogenesis in genetically predestinated offspring and to develop into applications against lethal neonatal cancer diseases for which powerful therapeutic options are currently unavailable.