Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells

Doyonnas, Régis; Nielsen, Julie S.; Chelliah, Shierley; Drew, Erin; Hara, Takahiko; Miyajima, Atsushi; McNagny, Kelly M.

doi:10.1182/blood-2004-10-4077

Cited by 111 publications

(102 citation statements)

References 44 publications

(59 reference statements)

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“…48 In renal podocytes, PODXL is thought to function in maintaining diaphragm slits. 49 In contrast, in hematopoietic stem cells 50 and potentially in certain cancers (eg, prostate and certain leukemias), 51,52 PODXL may act as an adhesion and/or cell migration factor. It therefore might be speculated through correlation that PODXL, as persistently induced by CNTO 530, may affect the residency of erythroid progenitors in marrow.…”

Section: Discussionmentioning

confidence: 99%

CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools

Sathyanarayana

Houde

Marshall³

et al. 2009

Blood

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Anemia as associated with numerous clinical conditions can be debilitating, but frequently can be treated via administration of epoetin-alfa, darbepoietin-alfa, or methoxy-PEG epoetin-beta. Despite the complexity of EPO-EPO receptor interactions, the development of interesting EPO mimetic peptides (EMPs) also has been possible. CNTO 530 is one such novel MIMETIBODY Fc-domain dimeric EMP fusion protein. In a mouse model, singledose CNTO 530 (unlike epoetin-alfa or darbepoietin-alfa) bolstered red cell production for up to 1 month. In 5-fluorouracil and carboplatin-paclitaxel models, CNTO 530 also protected against anemia with unique efficiency. These actions were not fully accounted for by half-life estimates, and CNTO 530 signaling events therefore were studied. Within primary bone marrow erythroblasts, kinetics of STAT5, ERK, and AKT activation were similar for CNTO 530 and epoetin-alfa. p70S6K activation by CNTO 530, however, was selectively sustained. In vivo, CNTO 530 uniquely stimulated the enhanced formation of PODXL high CD71 high (pro)erythroblasts at frequencies multifold above epoetin-alfa or darbepoietin-alfa. CNTO 530 moreover supported the sustained expansion of a bone marrow-resident Kit neg CD71 high Ter119 neg progenitor pool. Based on these distinct erythropoietic and EPOR signaling properties, CNTO 530 holds excellent promise as a new EPO mimetic. IntroductionAs recombinant injectables, epoetin-alfa and darbepoietin-alfa are important therapeutics for anemia. 1,2 Via its canonical dimeric single-transmembrane receptor (EPOR), 3,4 and possibly a hypothesized accessory chain, 5,6 erythropoietin (EPO) also has been shown to confer significant cytoprotection for certain injured nonhematopoietic tissues. 7 This includes renal, cardiac, brain, and retinal cells as damaged by ischemia, neurotoxins, or UV irradiation. [8][9][10][11] However, epoetin-alfa can require frequent injections in anemia contexts, as well as relatively high dosing to cytoprotect nonhematopoietic cells. 7 To address these issues, several EPOrelated erythropoiesis stimulating agents (ESAs) recently have been formulated and shown to possess one, or another, advantaged property. One orthologue is darbepoietin-alfa in which nonessential residues are mutated to provide for 2 additional N-linked glycosylation sites. 12 This can enhance darbepoietin-alfa's in vivo halflife, 13 and EPO receptor occupancy. 14 Together, these properties can lessen dosing frequency. 13 A second example is provided by "Epo-Epo" in which EPO is configured as a peptide-linked head-to-tail dimer. 15 For Epo-Epo, unique properties include enhanced secretion and apparent advantaged in vivo activity after subcutaneous injection. 16 In addition, a pegylated epoetin-beta has been developed (CERA) that possesses a significantly extended half-life, 17 and likewise can be effectively used with less frequent dosing. 18 A distinct approach to preparing ESAs involves the development of monoclonal antibodies that can bind and activate the EPOR. In particular, Liu et al 1...

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Section: Discussionmentioning

confidence: 99%

CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools

Sathyanarayana

Houde

Marshall³

et al. 2009

Blood

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“…For example, in the hematopoietic system, they facilitate cell migration and prevent nonspecific adhesion. 11,31,32 Interestingly, we also defined a novel role for podocalyxin in establishing cell morphology. 33 When expressed ectopically in breast or kidney epithelial cells, podocalyxin dramatically increases microvillus formation (Figure 2A).…”

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confidence: 90%

The Role of Podocalyxin in Health and Disease

Nielsen¹,

McNagny

2009

Journal of the American Society of Nephrology

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“…PODXL was initially identified in podocytes of renal glomeruli that are instrumental in kidney development (25,26 expression of PODXL was identified in podocytes, hematopoietic progenitors, vascular endothelia and embryonic stem cells (27)(28)(29)(30) and it was reported to promote anti-adhesive and migratory characteristics of various cancer cells except for pancreatic cancer (31)(32)(33)(34)(35). Recent studies showed that increased expression of PODXL is correlated with poor prognoses in many types of cancer (36)(37)(38)(39)(40)(41).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL

Chijiiwa

Moriyama

Ohuchida

et al. 2016

International Journal of Oncology

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Abstract.Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P= 0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.

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Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells

Cited by 111 publications

References 44 publications

CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools

CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools

The Role of Podocalyxin in Health and Disease

Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL

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