HP59 is a pathologic angiogenesis capillary endothelial marker protein (7 or 12 transmembrane domains)[1] which has been identified as the receptor for the Group B Streptococcal Toxin (GBS Toxin) molecule known as CM101,[2] the etiologic agent for early-onset versus late-onset Group B Strep.[2]
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Expression edit
Fu, et al. coined the term "pathological angiogenesis" to distinguish between HP59-expressing, and non-HP59-expressing capillaries, however, other researchers have not used this terminology.[1] Therefore it is not yet known whether HP59 is expressed in vasculogenesis, arteriogenesis, sprouting angiogenesis or intussusceptive angiogenesis. However capillaries in all tumor tissues examined were positive for anti-HP59 antibodies and Von Willebrand factor (vWF) antibodies, while in normal tissues only vWF staining was observed.[1]
The target protein for GBStoxin/CM101 is expressed in vasculature of developing organs during their formation during embryogenesis. The lung is the last organ to develop so HP59 is present in the newborn lung for 5–10 days after birth, explaining the susceptibility to GBS induced "early onset" disease. HP59 lectin is expressed later in life only in pathologic angiogenesis, providing a receptor for CM101. The CM101-HP59 complex then activates complement, and initiates an inflammatory cytokine cascade which recruits CD69 positive activated granulocytes to destroy the capillaries and surrounding pathologic tissue.[3] CM101 has been shown in a published Phase I, FDA-approved clinical trial under IND to have clinical safety and effectivity on select stage IV cancer patients, specifically targeting tumor vasculature[4]
HP59 is expressed in the adult in wound healing,[5] and in tumor angiogenesis, as shown in mice.[6]
The gene for HP59 contains, entirely within its coding region, the Sialin Gene SLC17A5 (Solute carrier family 17 (anion/sugar transporter). Member 5, also known asSLC17A5 or sialin is a lysosomal membrane sialic acid transport protein which in humans is encoded by the SLC17A5 gene on Chromosome 6,[7][8][9][10] and appears to be important in CNS myelination.[11] HP59 has a transcription initiation site 300bp upstream of the initiation site for the Sialin Gene SLC17A5, and encodes 41 additional aminoacids at the Amino-terminal.[1] Thus, using an upstream transcription initiation site, and thus a different start codon, HP59, incorporating the Sialin gene product, becomes a pathologic angiogenesis capillary endothelial cell luminal membrane protein with unknown function, which the GBS Toxin CM101 specifically targets. Endothelial involvement is indicated by levels of Soluble E-Selectin.[12]
References edit
- ^ a b c d Fu C, Bardhan S, Cetateanu ND, Wamil BD, Wang Y, Yan HP, Shi E, Carter C, Venkov C, Yakes FM, Page DL, Lloyd RS, Mernaugh RL, Hellerqvist CG (2001). "Identification of a Novel Membrane Protein HP59 with Therapeutic Potential as a Target of Tumor Angiogenesis". Clinical Cancer Research. 7 (12): 4182–4194. PMID 11751519.
- ^ a b Sundell HW, Yan H, Carter CE, Wamil BD, Wu K, Gaddipati R, Li D, Hellerqvist CG (2000). "Isolation and identification of group B β-hemolytic streptococcal (GBS) toxin from septic newborn infants". The Journal of Pediatrics. 137 (3): 338–344. doi:10.1067/mpd.2000.107839. PMID 10969257.
- ^ Yan HP, Carter CE, Wang EZ, Page DL, Washington K, Wamil BD, Yakes FM, Thurman GB, Hellerqvist CG (1998). "Functional studies on the anti-pathoangiogenic properties of CM101". Angiogenesis. 2 (3): 219–233. doi:10.1023/A:1009258801899. PMID 14517462. S2CID 21230380.
- ^ DeVore RF, Hellerqvist CG, Wakefield GB, Wamil BD, Thurman GB, Minton PA, Sundell HW, Yan HP, Carter CE, Wang YF, York GE, Zhang MH, Johnson DH (1997). "A phase I study of the antineovascularization drug CM101". J. Clin. Cancer Res. 3 (3): 365–372. PMID 9815693.
- ^ Nanney LB, Wamil BD, Whitsitt J, Cardwell NL, Davidson JM, Yan HP, Hellerqvist CG (2001). "CM101 Stimulates Cutaneous Wound Healing Through an Anti-Angiogenic Mechanism". Angiogenesis. 4 (1): 61–70. doi:10.1023/A:1016752925761. PMID 11824380. S2CID 25436212.
- ^ Thurman, GB; Russell, BA; York, GE; Wang, Y-F; Page, DL; Sundell, HW; Hellerqvist, CG (1994). "Effects of GBS toxin on long-term survival of mice bearing transplanted Madison lung tumors". J. Cancer Res. Clin. Oncol. 120 (8): 479–484. doi:10.1007/BF01191801. PMID 8207046. S2CID 1257221.
- ^ "Homo sapiens chromosome 6 genomic contig, GRCh37.p13 Primary Assembly". 2013-08-13.
{{cite journal}}: Cite journal requires|journal=(help) - ^ [1]"Entrez Gene: SLC17A5 solute carrier family 17 (anion/sugar transporter), member 5"
- ^ Haataja L, Schleutker J, Laine AP, Renlund M, Savontaus ML, Dib C, Weissenbach J, Peltonen L, Aula P (1994). "The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6". American Journal of Human Genetics. 54 (6): 1042–49. PMC 1918202. PMID 8198127.
- ^ Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GM (1999). "A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases". Nature Genetics. 23 (4): 462–65. doi:10.1038/70585. PMID 10581036. S2CID 5709302.
- ^ Prolo LM, Vogel H, Reimer RJ (2009). "The lysosomal sialic acid transporter sialin is required for normal CNS myelination". J. Neurosci. 29 (49): 15355–15365. doi:10.1523/JNEUROSCI.3005-09.2009. PMC 2820501. PMID 20007460.
- ^ Wamil BD, Thurman GB, Sundell HW, DeVore RF, Wakefield G, Johnson DH, Wang YF, Hellerqvist CG (1997). "Soluble E-selectin in cancer patients as a marker of the therapeutic efficacy of CM101, a tumor-inhibiting anti-neovascularization agent, evaluated in phase I clinical trial". J. Cancer Res. Clin. Oncol. 123 (3): 173–79. doi:10.1007/BF01214670. PMID 9119883. S2CID 30926947.