Abstract

Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ∼2.35 × 106 motifs recovered from biopsies yielded a nonrandom distribution, indicating that systemic tissue targeting is feasible. High-throughput analysis by similarity search, protein arrays, and affinity chromatography revealed four native ligand-receptors, three of which were previously unrecognized. Two are shared among multiple tissues (integrin α4/annexin A4 and cathepsin B/apolipoprotein E3) and the other two have a restricted and specific distribution in normal tissue (prohibitin/annexin A2 in white adipose tissue) or cancer (RAGE/leukocyte proteinase-3 in bone metastases). These findings provide vascular molecular markers for biotechnology and medical applications.

Continue Reading

Acknowledgments.

We thank Drs. Ricardo Brentani, Webster Cavenee, Roy Lobb, and Helene Sage for manuscript reading and David Bier, Pauline Dieringer, Cherie Perez, and Dallas Williams for infrastructure. This work was supported by grants from the National Institutes of Health, National Cancer Institute, Department of Defense, and by awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation.

Supporting Information

Supporting Information (PDF)
Supporting Information

References

1
M Barrios-Rodiles, et al., High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307, 1621–1625 (2005).
2
U Stelzl, et al., A human protein-protein interaction network: a resource for annotating the proteome. Cell 122, 957–968 (2005).
3
JF Rual, et al., Towards a proteome-scale map of the human protein-protein interaction network. Nature 437, 1173–1178 (2005).
4
A Breitkreutz, et al., A global protein kinase and phosphatase interaction network in yeast. Science 328, 1043–1046 (2010).
5
BR Zetter, The cellular basis of site-specific tumor metastasis. N Engl J Med 322, 605–612 (1990).
6
W Risau, I Flamme, Vasculogenesis. Annu Rev Cell Dev Biol 11, 73–91 (1995).
7
J Folkman, Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6, 273–286 (2007).
8
MG Kolonin, PK Saha, L Chan, R Pasqualini, W Arap, Reversal of obesity by targeted ablation of adipose tissue. Nat Med 10, 625–632 (2004).
9
FI Staquicini, R Pasqualini, W Arap, Ligand-directed profiling: applications to target drug discovery in cancer. Expert Opin Drug Dis 4, 51–59 (2009).
10
R Pasqualini, E Ruoslahti, Organ targeting in vivo using phage display peptide libraries. Nature 380, 364–366 (1996).
11
GP Smith, JK Scott, Libraries of peptides and proteins displayed on filamentous phage. Methods Enzymol 217, 228–257 (1993).
12
W Arap, et al., Steps toward mapping the human vasculature by phage display. Nat Med 8, 121–127 (2002).
13
AJ Zurita, et al., Combinatorial screenings in patients: the interleukin-11 receptor alpha as a candidate target in the progression of human prostate cancer. Cancer Res 64, 435–439 (2004).
14
RD Pentz, AL Flamm, R Pasqualini, CJ Logothetis, W Arap, Revisiting technical guidelines for research with terminal wean and brain-dead patients. Hastings Cent Rep 33, 20–26 (2003).
15
RD Pentz, et al., Ethics guidelines for research with the recently dead. Nat Med 11, 1145–1149 (2005).
16
MG Kolonin, et al., Synchronous selection of homing peptides for multiple tissues by in vivo phage display. FASEB J 20, 979–981 (2006).
17
E Dias-Neto, et al., Next-generation phage display: integrating and comparing available molecular tools to enable cost-effective high-throughput analysis. PLoS One 4, 1–11 (2009).
18
M Vendruscolo, E Paci, CM Dobson, M Karplus, Three key residues form a critical contact network in a protein folding transition state. Nature 409, 641–645 (2001).
19
MA Swairjo, BA Seaton, Annexin structure and membrane interactions: a molecular perspective. Annu Rev Biophys Biomol Struct 23, 193–213 (1994).
20
RD Burgoyne, MJ Geisow, The annexin family of calcium-binding proteins. Review article. Cell Calcium 10, 1–10 (1989).
21
DM Rose, R Alon, MH Ginsberg, Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev 218, 126–134 (2007).
22
BJ van Vlijmen, et al., Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice. J Clin Invest 93, 1403–1410 (1994).
23
SPM Lutgens, KB Cleutjens, MJ Daemen, S Heeneman, Cathepsin cysteine proteases in cardiovascular disease. FASEB J 21, 3029–3041 (2007).
24
J Liu, SM Deyoung, M Zhang, LH Dold, AR Saltiel, The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. J Biol Chem 280, 16125–16134 (2005).
25
J Zhang, KR McCrae, Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies. Blood 105, 1964–1969 (2005).
26
JJ Molldrem, et al., Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6, 1018–1023 (2000).
27
D Campanelli, et al., Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils. J Exp Med 172, 1709–1715 (1990).
28
HJ Huttunen, C Fages, J Kuja-Panula, AJ Ridley, H Rauvala, Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res 62, 4805–4811 (2002).
29
H Ishiguro, et al., Receptor for advanced glycation end products (RAGE) and its ligand, amphoterin are overexpressed and associated with prostate cancer development. Prostate 64, 92–100 (2005).
30
YJ Jeon, et al., Annexin A4 interacts with NF-kappaB p50 subunit and modulates NF-kappaB transcriptional activity in a Ca+-dependent manner. Cell Mol Life Sci 67, 2271–2281 (2010).
31
RR Lobb, ME Hemler, The pathophysiologic role of α4 integrins in vivo. J Clin Invest 94, 1722–1728 (1994).
32
G Gorfu, J Rivera-Nieves, K Ley, Role of β7 integrins in intestinal lymphocyte homing and retention. Curr Mol Med 9, 836–850 (2009).
33
DM Hatters, CA Peters-Libeu, KH Weisgraber, Apolipoprotein E structure: insights into function. Trends Biochem Sci 31, 445–454 (2006).
34
S Bacher, G Achatz, ML Schmitz, MC Lamers, Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2. Biochimie 84, 1207–1220 (2002).
35
DH Kim, SC Woods, RJ Seeley, Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight. Diabetes 59, 907–915 (2010).
36
A Uehara, Y Sugawara, T Sasano, H Takada, S Sugawara, Proinflammatory cytokines induce proteinase 3 as membrane-bound and secretory forms in human oral epithelial cells and antibodies to proteinase 3 activate the cells through protease-activated receptor-2. J Immunol 173, 4179–4189 (2004).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 108 | No. 46
November 15, 2011
PubMed: 22049339

Classifications

Submission history

Published online: November 2, 2011
Published in issue: November 15, 2011

Keywords

  1. human disease
  2. phage display
  3. obesity
  4. angiogenesis
  5. tumor

Acknowledgments

We thank Drs. Ricardo Brentani, Webster Cavenee, Roy Lobb, and Helene Sage for manuscript reading and David Bier, Pauline Dieringer, Cherie Perez, and Dallas Williams for infrastructure. This work was supported by grants from the National Institutes of Health, National Cancer Institute, Department of Defense, and by awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation.

Authors

Affiliations

Fernanda I. Staquicini1
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Marina Cardó-Vila1
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Mikhail G. Kolonin1
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Present address: Institute of Molecular Medicine, University of Texas, Houston, TX 77030.
Martin Trepel
Department of Oncology and Hematology, University Medical Center of Hamburg, 20246 Hamburg, Germany;
Julianna K. Edwards
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Diana N. Nunes
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Present address: A.C. Camargo Hospital, São Paulo, Brazil 01509-010.
Anna Sergeeva
Department of Stem Cell Transplantation;
Eleni Efstathiou
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Jessica Sun
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Nalvo F. Almeida
Virginia Bioinformatics Institute and Department of Computer Science, Virginia Polytechnic University, Blacksburg, VA 24060;
Shi-Ming Tu
Department of Genitourinary Medical Oncology;
Gregory H. Botz
Department of Critical Care;
Michael J. Wallace
Department of Diagnostic Radiology;
David J. O’Connell
Conway Institute of Biomedical and Biomolecular Science, University College Dublin, Belfield, Dublin 4, Ireland;
Stan Krajewski
Cancer Center, The Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and
Jeffrey E. Gershenwald
Department of Surgical Oncology;
Jeffrey J. Molldrem
Department of Stem Cell Transplantation;
Anne L. Flamm
Department of Clinical Ethics;
Present address: Cleveland Clinic, Cleveland, OH 44195.
Erkki Koivunen
Department of Leukemia;
Rebecca D. Pentz
Department of Clinical Ethics;
Present address: Winship Cancer Institute, Emory University, Atlanta, GA 30322.
Emmanuel Dias-Neto
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Present address: A.C. Camargo Hospital, São Paulo, Brazil 01509-010.
João C. Setubal
Virginia Bioinformatics Institute and Department of Computer Science, Virginia Polytechnic University, Blacksburg, VA 24060;
Dolores J. Cahill
Conway Institute of Biomedical and Biomolecular Science, University College Dublin, Belfield, Dublin 4, Ireland;
Patricia Troncoso
Department of Pathology;
Kim-Ahn Do
Department of Biostatistics;
Christopher J. Logothetis
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Richard L. Sidman2 [email protected]
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
Renata Pasqualini2,1 [email protected]
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
David H. Koch Center;
Department of Genitourinary Medical Oncology;
Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;

Notes

2
To whom correspondence may be addressed. E-mail: [email protected], or [email protected], or [email protected].
Contributed by Richard L. Sidman, September 12, 2011 (sent for review March 28, 2011)
Author contributions: F.I.S., M.C.V., M.G.K., E.K., D.J.C., R.L.S., W.A., and R.P. designed research; F.I.S., M.C.V., M.G.K., J.K.E., D.N.N., A.S., E.E., S.-M.T., G.H.B., M.J.W., D.J.O., S.K., J.E.G., and E.D.-N. performed research; F.I.S., M.C.V., M.G.K., M.T., J.K.E., D.N.N., A.S., E.E., J.S., N.F.A., D.J.O., J.J.M., A.L.F., E.K., R.D.P., E.D.-N., J.C.S., D.J.C., P.T., K.-A.D., C.J.L., R.L.S., W.A., and R.P. analyzed data; and F.I.S., M.C.V., M.G.K., R.L.S., W.A., and R.P. wrote the paper.
1
F.I.S., M.C.V., M.G.K., R.P., and W.A. contributed equally to this work.

Competing Interests

Conflict of interest statement: The University of Texas M.D. Anderson Cancer Center and some of its researchers (W.A. and R.P.) have equity positions in and are paid consultants for Alvos Therapeutics and Ablaris Therapeutics, which are subjected to certain restrictions under university policy; the university manages and monitors the terms of these arrangements in accordance with its conflict-of-interest policy.

Metrics & Citations

Metrics

Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to ths delay, usage data will not appear immediately following publication. Citation information is sourced from Crossref Cited-by service.


Citation statements

Altmetrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

Cited by

    Loading...

    View Options

    View options

    PDF format

    Download this article as a PDF file

    DOWNLOAD PDF

    Get Access

    Login options

    Check if you have access through your login credentials or your institution to get full access on this article.

    Personal login Institutional Login

    Recommend to a librarian

    Recommend PNAS to a Librarian

    Purchase options

    Purchase this article to get full access to it.

    Single Article Purchase

    Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients
    Proceedings of the National Academy of Sciences
    • Vol. 108
    • No. 46
    • pp. 18567-18854

    Media

    Figures

    Tables

    Other

    Share

    Share

    Share article link

    Share on social media