The melanoma tumor antigen, melanotransferrin (p97): a 25-year hallmark – from iron metabolism to tumorigenesis

Rahmanto, Yohan Suryo; Dunn, Louise; Richardson, Des R.

doi:10.1038/sj.onc.1210442

Cited by 54 publications

(28 citation statements)

References 98 publications

(162 reference statements)

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“…MFI2 (melanotransferrin) is a transferrin superfamily protein with a single high-affinity iron (III)-binding site that is required for cancer cell growth and proliferation. Down regulation of MFI2 in melanoma cells by post-transcriptional gene silencing slows cell growth and leads to inhibition of DNA synthesis [52]. Conceivably, the low expression of MFI2 in PC3 holoclones and spheres could contribute to the self-renewal and lack of differentiation of the CSC population.…”

Section: Discussionmentioning

confidence: 99%

PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis

Zhang

Waxman

2010

Mol Cancer

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BackgroundCancer stem-like cells are proposed to sustain solid tumors by virtue of their capacity for self-renewal and differentiation to cells that comprise the bulk of the tumor, and have been identified for a variety of cancers based on characteristic clonal morphologies and patterns of marker gene expression.MethodsSingle cell cloning and spheroid culture studies were used to identify a population of cancer stem-like cells in the androgen-independent human prostate cancer cell line PC3.ResultsWe demonstrate that, under standard culture conditions, ~10% of PC3 cells form holoclones with cancer stem cell characteristics. These holoclones display high self-renewal capability in spheroid formation assays under low attachment and serum-free culture conditions, retain their holoclone morphology when passaged at high cell density, exhibit moderate drug resistance, and show high tumorigenicity in scid immunodeficient mice. PC3 holoclones readily form spheres, and PC3-derived spheres yield a high percentage of holoclones, further supporting their cancer stem cell-like nature. We identified one gene, FAM65B, whose expression is consistently up regulated in PC3 holoclones compared to paraclones, the major cell morphology in the parental PC3 cell population, and two genes, MFI2 and LEF1, that are consistently down regulated. This molecular profile, FAM65Bhigh/MFI2low/LEF1low, also characterizes spheres generated from parental PC3 cells. The PC3 holoclones did not show significant enriched expression of the putative prostate cancer stem cell markers CD44 and integrin α2β1. PC3 tumors seeded with holoclones showed dramatic down regulation of FAM65B and dramatic up regulation of MFI2 and LEF1, and unexpectedly, a marked increase in tumor vascularity compared to parental PC3 tumors, suggesting a role of cancer stem cells in tumor angiogenesis.ConclusionsThese findings support the proposal that PC3 tumors are sustained by a small number of tumor-initiating cells with stem-like characteristics, including strong self-renewal and pro-angiogenic capability and marked by the expression pattern FAM65Bhigh/MFI2low/LEF1low. These markers may serve as targets for therapies designed to eliminate cancer stem cell populations associated with aggressive, androgen-independent prostate tumors such as PC3.

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Section: Discussionmentioning

confidence: 99%

PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis

Zhang

Waxman

2010

Mol Cancer

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“…Similar to the linkage of the different transferrin genes in mammals and chicken [54], the Ciona nicaTf and Tf -like genes are both located on chromosome 7q [43], but we were not able to find any syntenic segments between these linkage groups. In contrast, the fish Tf , MTf and Omp genes are positioned on three linkage groups, and the Omp flanking genes Senp2 , Tra2b and D2hgdh are closely linked to chicken Tf on chromosome 9, while Senp2 , Tra2b and Slitrk3 are flanked by human MTF and Tf on chromosome 3 (Figure 2).…”

Section: Discussionmentioning

confidence: 69%

Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua) - Conserved synteny between fish monolobal and tetrapod bilobal transferrin loci

et al. 2011

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BackgroundThe two homologous iron-binding lobes of transferrins are thought to have evolved by gene duplication of an ancestral monolobal form, but any conserved synteny between bilobal and monolobal transferrin loci remains unexplored. The important role played by transferrin in the resistance to invading pathogens makes this polymorphic gene a highly valuable candidate for studying adaptive divergence among local populations.ResultsThe Atlantic cod genome was shown to harbour two tandem duplicated serum transferrin genes (Tf1, Tf2), a melanotransferrin gene (MTf), and a monolobal transferrin gene (Omp). Whereas Tf1 and Tf2 were differentially expressed in liver and brain, the Omp transcript was restricted to the otoliths. Fish, chicken and mammals showed highly conserved syntenic regions in which monolobal and bilobal transferrins reside, but contrasting with tetrapods, the fish transferrin genes are positioned on three different linkage groups. Sequence alignment of cod Tf1 cDNAs from Northeast (NE) and Northwest (NW) Atlantic populations revealed 22 single nucleotide polymorphisms (SNP) causing the replacement of 16 amino acids, including eight surface residues revealed by the modelled 3D-structures, that might influence the binding of pathogens for removal of iron. SNP analysis of a total of 375 individuals from 14 trans-Atlantic populations showed that the Tf1-NE variant was almost fixed in the Baltic cod and predominated in the other NE Atlantic populations, whereas the NW Atlantic populations were more heterozygous and showed high frequencies of the Tf-NW SNP alleles.ConclusionsThe highly conserved synteny between fish and tetrapod transferrin loci infers that the fusion of tandem duplicated Omp-like genes gave rise to the modern transferrins. The multiple nonsynonymous substitutions in cod Tf1 with putative structural effects, together with highly divergent allele frequencies among different cod populations, strongly suggest evidence for positive selection and local adaptation in trans-Atlantic cod populations.

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“…Furthermore, histological examination of ABCB5 + melanoma cell-derived primary and secondary xenograft tumors revealed phenotypic heterogeneity resembling that of the respective parent tumors [6]. The identified association of ABCB5 expression with tumorigenesis is consistent with findings of close co-regulation of ABCB5 with melanoma tumor antigen p97 (melanotransferrin (MTf)), a known regulator of tumor growth [21] and with preferential ABCB5 expression also by in vitro clonogenic, self-renewing melanoma cell subsets [22]. Furthermore, it is consistent with the downregulation of ABCB5 with induced terminal differentiation and the concomitant loss of growth potential and chemoresistance of human melanoma cells [23].…”

Section: Malignant Melanoma and Cancer Stem Cellsmentioning

confidence: 70%

Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

Ma¹,

Frank²

2010

ACAMC

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Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanomainitiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.

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The melanoma tumor antigen, melanotransferrin (p97): a 25-year hallmark – from iron metabolism to tumorigenesis

Cited by 54 publications

References 98 publications

PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis

PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis

Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua) - Conserved synteny between fish monolobal and tetrapod bilobal transferrin loci

Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

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