The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers
Carl G. Hellerqvist, Ph.D.
Prof Biochemistry & Med
VICC Member
Researcher
Contact Information:
Vanderbilt University Medical Center
634 Robinson Research Building
Nashville, TN 37232-0146
615-322-4339
Research Specialty
Identification of an anti-pathoangiogenic agent and its target protein with applications in cancer, RA, ulcers and paralysis.
Research Description
Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101), which we have previously described as GBS Toxin. We have recently demonstrated with an ELISA assay that CM101 is present at high concentrations in the plasma and spinal fluid of neonates diagnosed with GBS sepsis. Furthermore, we isolated large quantities of biologically active CM101 from the neonate's urine. We are currently exploring means to block the respiratory distress with direct application to the nursery.
We hypothesized early that CM101 would bind to embryonic receptors in the neonatal lung and would bind to the neovasculature in human tumors. CM101 binds in vivo to the vasculature of human tumors, and in a mouse tumor model causes inflammatory reactions at the tumor site that lead to retarded tumor growth or regression depending on treatment regiment. CM101 treatment, in cancer patients in Phase I clinical trials and in tumor bearing mice over-rides the tumor immunoprivilege, which allows the tumor to grow, and allows inflammatory cells to invade the tumor and induce tumor apoptosis and ablation.
Current research is aimed at an understanding the molecular biology of the anti-pathoangiogenic properties of CM101. We have research interests in several areas:
I. Spinal Cord Injury. CM101 by inhibiting inflammatory angiogenesis prevents secondary inflammatory injury to the spinal cord and scarring. This allows animals to recover from paralysis. CM101 by the same mechanism accelerates wound healing and prevents scar formation. The mechanisms of these events are under investigation.
II. Stem Cell Transplantation in Chronic Spinal Cord Injury. By a mechanism not quite understood, CM101 in picomolar concentration stimulates the differentiation of stem cells into neurons. When these neurons are transferred to the spinal cord cavity created by surgical removal of the gliosis in chronically paralyzed mice, which are treated with i.v. infusions of CM101, the animals show remarkable recovery of motor and sensory function. Functional MRI is being applied to demonstrate the neuronal recovery. The mechanism of CM101 induced differentiation into neurons is under investigation.
III. Clinical and pre-clinical data reveals that the inflammatory response induced by CM101 binding to a target protein in the pathologic vasculature initiates a break down of the immunoprivilege the tumor has created in the host. Leukocyte p53 mRNA is up regulated and tumor apoptosis is induced in p53 negative tumors. The mechanism of this induction remains unsolved.
IV. We have expression cloned the target protein HP59, which CM101 binds to and are addressing the pathophysiology seen in our animal models and in patients in response to CM101 treatment. We have demonstrated by immunohistochemistry that HP59 is uniquely present only in pathologic angiogenesis and aim to develop specific targeting agents for drug development.
V. We have initiated a vaccine program where mice are immunized with HP59-derived peptides. We have attenuated growth of subq implanted tumors by inhibiting angiogenesis and vasculogenesis and i.v. challenges with melanoma cells are not lethal to other immunized mice. These tumor resistant mice have given birth to normal size litter demonstrating that the pathologic and physiologic angiogenesis are distinctly different in expression of HP59.
VI. We are applying our immunization model to better understand the anti-pathoangiogenic properties of CM101 which makes it applicable to rheumatoid arthritis, wound healing, reperfusion injury, spinal cord injury and other diseases driven by pathologic angiogenesis.
Publications
- Ohlsson, Marcus, Mattsson, Per, Wamil, Barbara D, Hellerqvist, Carl G, Svensson, Mikael Macrophage stimulation using a group B-streptococcus exotoxin (CM101) leads to axonal regrowth in the injured optic nerve. Restor Neurol Neurosci, 22(1), 33-41, 2004.
- Nanney, L B, Wamil, B D, Whitsitt, J, Cardwell, N L, Davidson, J M, Yan, H P, Hellerqvist, C G CM101 stimulates cutaneous wound healing through an anti-angiogenic mechanism. Angiogenesis, 4(1), 61-70, 2001.
- Fu, C, Bardhan, S, Cetateanu, N D, Wamil, B D, Wang, Y, Yan, H P, Shi, E, Carter, C, Venkov, C, Yakes, F M, Page, D L, Lloyd, R S, Mernaugh, R L, Hellerqvist, C G Identification of a novel membrane protein, HP59, with therapeutic potential as a target of tumor angiogenesis. Clin Cancer Res, 7(12), 4182-94, 2001.
- Yakes, F M, Wamil, B D, Sun, F, Yan, H P, Carter, C E, Hellerqvist, C G CM101 treatment overrides tumor-induced immunoprivilege leading to apoptosis. Cancer Res, 60(20), 5740-6, 2000.
- Sundell, H W, Yan, H, Carter, C E, Wamil, B D, Wu, K, Gaddipati, R, Li, D, Hellerqvist, C G Isolation and identification of the group B streptococcal toxin CM101 from infants with sepsis. J Pediatr, 137(3), 338-44, 2000.
- Fleischer, A C, Wojcicki, W E, Donnelly, E F, Pickens, D R, Thirsk, G, Thurman, G B, Hellerqvist, C G Quantified color Doppler sonography of tumor vascularity in an animal model. J Ultrasound Med, 18(8), 547-51, 1999.
- Wamil, A W, Wamil, B D, Hellerqvist, C G CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury. Proc Natl Acad Sci U S A, 95(22), 13188-93, 1998.
- Yan, H P, Carter, C E, Wang, E Z, Page, D L, Washington, K, Wamil, B D, Yakes, F M, Thurman, G B, Hellerqvist, C G Functional studies on the anti-pathoangiogenic properties of CM101. Angiogenesis, 2(3), 219-33, 1998.
- Hellerqvist, C.G "CM101 - An Anti-Pathoangiogenic Agent: Pre-clinical and Clinical Experiences." NATO/ASI Series - Angiogenesis: Models, Modulators, and Clinical Applications. M.E. Maragoudakis, P.M. Gullino and P.I. Lelkes, Eds. Plenum Press Publishers, New York and London. Series A: Life Sciences, 1997.
- DeVore, R F, Hellerqvist, C G, Wakefield, G B, Wamil, B D, Thurman, G B, Minton, P A, Sundell, H W, Yan, H P, Carter, C E, Wang, Y F, York, G E, Zhang, M H, Johnson, D H Phase I study of the antineovascularization drug CM101. Clin Cancer Res, 3(3), 365-72, 1997.
- Wamil, B D, Thurman, G B, Sundell, H W, DeVore, R F, Wakefield, G, Johnson, D H, Wang, Y F, Hellerqvist, C G 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 trail. J Cancer Res Clin Oncol, 123(3), 173-9, 1997.
- Thurman, G B, Page, D L, Wamil, B D, Wilkinson, L E, Kasami, M, Hellerqvist, C G Acute inflammatory changes in subcutaneous microtumors in the ears of mice induced by intravenous CM101 (GBS toxin). J Cancer Res Clin Oncol, 122(9), 549-53, 1996.
- Hellerqvist, C G, Lloyd, R S, Wang, E, Bardhan, S Modulation of interleukin-12 mRNA expression in leukocytes of cancer patients treated with CM101. Ann N Y Acad Sci, 795346-8, 1996.
- Meyerowitz, C B, Fleischer, A C, Pickens, D R, Thurman, G B, Borowsky, A D, Thirsk, G, Hellerqvist, C G Quantification of tumor vascularity and flow with amplitude color Doppler sonography in an experimental model: preliminary results. J Ultrasound Med, 15(12), 827-33, 1996.
- Quinn, T E, Thurman, G B, Sundell, A K, Zhang, M, Hellerqvist, C G CM101, a polysaccharide antitumor agent, does not inhibit wound healing in murine models. J Cancer Res Clin Oncol, 121(4), 253-6, 1995.
- Thurman, G B, Russel, B A, York, G E, Wang, Y F, Page, D L, Sundell, H W, Hellerqvist, C G Effects of group B Streptococcus toxin on long-term survival of mice bearing transplanted Madison lung tumors. J Cancer Res Clin Oncol, 120(8), 479-84, 1994.
- Tamura, M, Harris, T M, Phillips, D, Blair, I A, Wang, Y F, Hellerqvist, C G, Lam, S K, Inagami, T Identification of two cardiac glycosides as Na(+)-pump inhibitors in rat urine and diet. J Biol Chem, 269(16), 11972-9, 1994.
- Sandberg, K., Edberg, K.E., Fish, W., Parker, R., Hellerqvist, C., and Sundell "Thromboxane Receptor Blockage (SQ 29548) in Group B Streptococcal (GBS) Toxin Challenge in Young Lambs." Pediatr. Res., 35571-579, 1994.
- Hellerqvist, C G, Thurman, G B, Page, D L, Wang, Y F, Russell, B A, Montgomery, C A, Sundell, H W Antitumor effects of GBS toxin: a polysaccharide exotoxin from group B beta-hemolytic streptococcus. J Cancer Res Clin Oncol, 120(1-2), 63-70, 1993.
- Hellerqvist, C G Linkage analysis using Lindberg method. Methods Enzymol, 193554-73, 1990.
- Hellerqvist, C G, Sweetman, B J Mass spectrometry of carbohydrates. Methods Biochem Anal, 3491-143, 1990.
- Pappas, R S, Sweetman, B J, Ray, S, Hellerqvist, C G Monomer sequence determination of carbohydrates using fast-atom bombardment mass spectrometry of periodate-oxidized acetate ester derivatives. Carbohydr Res, 1971-14, 1990.
- Cumming, D A, Hellerqvist, C G, Harris-Brandts, M, Michnick, S W, Carver, J P, Bendiak, B Structures of asparagine-linked oligosaccharides of the glycoprotein fetuin having sialic acid linked to N-acetylglucosamine. Biochemistry, 28(15), 6500-12, 1989.
- Hellerqvist, C G, Sundell, H, Gettins, P Molecular basis for group B beta-hemolytic streptococcal disease. Proc Natl Acad Sci U S A, 84(1), 51-5, 1987.
- Rojas, J, Palme, C, Ogletree, M L, Hellerqvist, C G, Brigham, K L, Stahlman, M T Effects of methylprednisolone on the response to group B streptococcal toxin in sheep. Pediatr Res, 18(11), 1141-4, 1984.
- Rojas, J, Larsson, L E, Hellerqvist, C G, Brigham, K L, Gray, M E, Stahlman, M T Pulmonary hemodynamic and ultrastructural changes associated with Group B streptococcal toxemia in adult sheep and newborn lambs. Pediatr Res, 17(12), 1002-8, 1983.
- Murthy, S V, Melly, M A, Harris, T M, Hellerqvist, C G, Hash, J H The repeating sequence of the capsular polysaccharide of Staphylococcus aureus M. Carbohydr Res, 117113-23, 1983.
- Hellerqvist, C G Biosynthetic matrices from cells in culture. Methods Enzymol, 82 Pt A530-5, 1982.
- Graber, S E, Hellerqvist, C G Direct evidence that bacterial lipopolysaccharides elevate cyclic GMP levels in rat fetal liver cells. J Biol Chem, 257(10), 5414-9, 1982.
- Cumming, D A, Hellerqvist, C G, Touster, O Identification of a 2-aminotetrose in a lipid-soluble fraction of rat liver. J Biol Chem, 256(15), 7723-6, 1981.
- Hellerqvist, C G, Rojas, J, Green, R S, Sell, S, Sundell, H, Stahlman, M T Studies on group B beta-hemolytic Streptococcus. I. Isolation and partial characterization of an extracellular toxin. Pediatr Res, 15(6), 892-8, 1981.
- Rojas, J, Green, R S, Hellerqvist, C G, Olegard, R, Brigham, K L, Stahlman, M T Studies on group B beta-hemolytic Streptococcus. II. Effects on pulmonary hemodynamics and vascular permeability in unanesthetized sheep. Pediatr Res, 15(6), 899-904, 1981.
- Krueger, K E, Hellerqvist, C G Studies on intercellular adhesion. Induction of adhesion by multivalent ligands. J Biol Chem, 256(16), 8553-60, 1981.
- Krueger, K E, Hellerqvist, C G Studies on intercellular adhesion. Mechanism of induction of cell adhesion. J Biol Chem, 256(20), 10684-9, 1981.
- Gregg, C R, Melly, M A, Hellerqvist, C G, Coniglio, J G, McGee, Z A Toxic activity of purified lipopolysaccharide of Neisseria gonorrhoeae for human fallopian tube mucosa. J Infect Dis, 143(3), 432-9, 1981.
- Lindberg, A A, Hellerqvist, C G Rough mutants of Salmonella typhimurium: immunochemical and structural analysis of lipopolysaccharides from rfaH mutants. J Gen Microbiol, 116(1), 25-32, 1980.
- Quinn, R W, Lowry, P N, Hellerqvist, C G Serologic groups of Neisseria gonorrhoeae recovered from patients in Nashville, Tennessee, 1971--1976. Sex Transm Dis, 7(2), 44-8, 1980.
- Schwartz, C E, Hellerqvist, C G, Cunningham, L W Attaching human fibroblasts secrete a type I procollagen rich in 3-hydroxyproline. Biochem Biophys Res Commun, 90(1), 240-6, 1979.
- Hellerqvist, C G Intercellular adhesion as a function of the cell cycle traverse. J Cell Biol, 82(3), 682-7, 1979.
- Schwartz, C E, Hoffman, L, Hellerqvist, C G, Cunningham, L W Scanning electron microscopic visualization of a microexudate prepared by the release of cells by urea. Exp Cell Res, 118(2), 427-30, 1979.
- Schwartz, C E, Hellerqvist, C G, Cunningham, L W A collagenous component of the microexudate carpet secreted by attaching human fibroblasts. Ann N Y Acad Sci, 312450-2, 1978.
- Rottmann, W L, Walther, B T, Hellerqvist, C G, Umbreit, J, Roseman, S A quantitative assay for concanavalin A-mediated cell agglutination. J Biol Chem, 249(2), 373-80, 1974.
- Hellerqvist, C G, Hoffman, J, Lindberg, A A, Lindberg, B, Svensson, S Sequence analysis of the polysaccharides from Salmonella newport and Salmonella kentucky. Acta Chem Scand, 26(8), 3282-6, 1972.
- Hellerqvist, C G, Lindberg, B, Samuelsson, K, Brubaker, R R Structural studies on the O-specific side-chains of the cell-wall lipopolysaccharide from Pasteurella pseudo-tuberculosis Group II A. Acta Chem Scand, 26(4), 1389-93, 1972.
- Hellerqvist, C G, Lindberg, B, Samuelsson, K, Brubaker, R R Structural studies on the O-specific side-chains of the cell-wall lipopolysaccharide from Pasteurella pseudo-tuberculosis Group II B. Acta Chem Scand, 26(4), 1394-8, 1972.
- Lindberg, A A, Holme, T, Hellerqvist, C G, Svensson, S Studies of a li-hapten isolated from cell-walls of the rough mutant Salmonella typhimurium 395 MR10. Acta Pathol Microbiol Scand [B] Microbiol Immunol, 80(5), 743-50, 1972.
- Hellerqvist, C G, Rudén, U, Mäkelä, P H The group C 2 -type modification of the B-type lipopolysaccharide in a hybrid between salmonella groups B and C 2. Eur J Biochem, 25(1), 96-101, 1972.
- Hellerqvist, C G, Hoffman, J, Lindberg, B, Pilotti, A, Lindberg, A A Anomeric nature of the D-mannose residues in the Salmonella typhi and S. strasbourg lipopolysaccharides. Acta Chem Scand, 25(4), 1512-3, 1971.
- Hakomori, S I, Siddiqui, B, Li, Y T, Li, S C, Hellerqvist, C G Anomeric structure of globoside and ceramide grihexoside of human erythrocytes and hamster fibroblasts. J Biol Chem, 246(7), 2271-7, 1971.
- Lindberg, A A, Hellerqvist, C G Bacteriophage attachment sites, serological specificity, and chemical composition of the lipopolysaccharides of semirough and rough mutants of Salmonella typhimurium. J Bacteriol, 105(1), 57-64, 1971.
- Hellerqvist, C G, Lindberg, B, Lönngren, J Fragmentation anallysis of the salmonella newport lipopolysaccharide. Acta Chem Scand, 25(2), 601-6, 1971.
- Hellerqvist, C G, Lindberg, B, Lönngren, J, Lindberg, A A Structural studies on the O-specific side-chains of the cell-wall lipopolysaccharide from Salmonella newington. Acta Chem Scand, 25(3), 939-44, 1971.
- Hellerqvist, C G, Lindberg, B, Samuelsson, K, Lindberg, A A Structural studies on the O-specific side-chains of the cell-wall lipopolysaccharide from Salmonella parathyphi A var. durazzo. Acta Chem Scand, 25(3), 955-61, 1971.
- Hellerqvist, C G, Larm, O, Lindberg, B Structure of an oligosaccharide obtained on degradation of the lipopolysaccharide from Salmonella typhimurium LT2. Acta Chem Scand, 25(2), 744-5, 1971.
- Nurminen, M, Hellerqvist, C G, Valtonen, V V, Mäkelä, P H The smooth lipopolysaccharide character of 1,4,(5),12 and 1,9,12 transductants formed as hybrids between groups B and D of salmonella. Eur J Biochem, 22(4), 500-5, 1971.
- Lindberg, A A, Holme, T, Hellerqvist, C G, Svensson, S Bacteriophage receptor development and synthesis of O-specific side chains after addition of D-galactose to the uridine diphosphate-galactose-4-epimeraseless mutant Salmonella typhimurium LT2-M1. J Bacteriol, 102(2), 540-7, 1970.
- Hellerqvist, C G, Lindberg, B, Pilotti, A, Lindberg, A A Structural studies on the O-specific side-chains of the cell-wall lipopolysaccharide from Salmonella strasbourg. Acta Chem Scand, 24(4), 1168-74, 1970.
- Berst, M, Hellerqvist, C G, Lindberg, B, Lüderitz, O, Svensson, S, Westphal, O Structural investigations on T1 lipopolysaccharides. Eur J Biochem, 11(2), 353-9, 1969.
- Hellerqvist, C G, Larm, O, Lindberg, B, Holme, T, Lindberg, A A Structural studies on the O-specific side chains of the cell wall lipopolysaccharide from Salmonella bredeney. Acta Chem Scand, 23(7), 2217-22, 1969.
- Hellerqvist, C G, Lindberg, B, Svensson, S, Holme, T, Lindberg, A A Structural studies on the O-specific side chains of the cell wall lipopolysaccharides from Salmonella typhi and S. enteritidis. Acta Chem Scand, 23(5), 1588-96, 1969.
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