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Differential gene expression in physiological and pathological angiogenesis

Inactive Publication Date: 2010-02-04
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]Methods are disclosed for delivering a therapeutic or diagnostic agent to liver endothelial cells. In particular examples, the method includes administering a therapeutically effective amount of a composition that includes a binding agent that specifically binds to one or more liver endothelial marker proteins (e.g., deoxyribonuclease 1-like 3, LZP oncoprotein induced transcript 3, putative transmembrane protein Accession No. NM—023438, CD32 15, putative G-protein coupled receptor NM—033616, C-type lectin-like receptor 2, C-type lectin domain family 4 member g 16, Plexin C1, Wnt9B, Accession No. AK144596, GATA-binding protein 4, MBL-associated serine protease-3, Renin binding protein, putative transmembrane protein Accession No. NM—144830, or Retinoic acid receptor, beta) and a therapeutic agent. Such a method can evoke a therapeutic response in the liver endothelial cells or permit detection of the cells.

Problems solved by technology

Tumor cells evolve resistance to cancer therapies due to genomic instability (high variation) and rapid generation time (days).
A remaining challenge, however, is to identify markers that can differentiate pathological and physiological angiogenesis in order to selectively deliver therapeutic agents to diseased tissues while minimizing the potential side effects of the targeted therapy.

Method used

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  • Differential gene expression in physiological and pathological angiogenesis
  • Differential gene expression in physiological and pathological angiogenesis
  • Differential gene expression in physiological and pathological angiogenesis

Examples

Experimental program
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example 1

Materials and Methods

[0258]Cell lines and animal studies. EMT6 cells were a kind gift of Dr. Robert S. Kerbel, KM12SM cells were a kind gift of Isaiah J. Fidler, HCT116 cells were from the DCT tumor repository (NCI, Frederick) and LS174T, SW620, CT26 and LLC were from the American Type Culture Collection (Manassas, Va.). Tumor cell lines were maintained in DMEM containing 10% fetal bovine serum. Tumors were made by inoculating 5×105−1×106 cells subcutaneously or intrasplenically. To produce liver metastasis by intrasplenic injection, the spleen was exteriorized through a left lateral incision prior to tumor cell injection. The tumor cell suspension was allowed to enter the portal circulation over a period of five minutes, after which the spleen was removed and the skin sutured. For partial hepatectomy, the liver was exposed through a midline abdominal incision and the two anterior lobes were exteriorized and the suspensory ligaments severed. The left lateral and caudal lobes were ge...

example 2

Purification of Endothelial Cells from Normal and Malignant Tissues

[0267]This example describes methods used to immunopurify endothelial cells (ECs) from various tissue types.

[0268]Initial attempts to purify ECs involved antibody recognition of CD31, the conventional cell surface marker used for affinity purification of mouse ECs, were difficult because of its cross reactivity with hematopoietic cells. CD105 (endoglin) and / or VE-cadherin were found to be specifically localized to the ECs of normal and tumor tissues. For example, as illustrated in FIG. 1A, immunofluorescence staining of heart tissue demonstrated co-localization of CD105 (green) with VE-cadherin (red) in the heart vessels. Further, FIG. 1B demonstrates immunofluorscence staining of liver tissue with CD105 (green). CD105 was determined to be a preferred marker in liver because CD105 stained all the endothelium including sinusoidal ECs whereas VE-cadherin did not.

[0269]The cell isolation involved tissue dissociation, th...

example 3

Gene Expression in Resting Normal ECs, Regenerating Liver ECs and Tumor ECs

[0277]This example illustrates the expression of various markers in resting normal ECs, regenerating liver ECs and tumor ECs.

[0278]In order to identify genes that were elevated during physiological angiogenesis, ECs were isolated from liver at 24-, 48- or 72-hours following partial hepatectomy, the period during which endothelial growth is thought to occur (Michalopoulos & DeFrances. Science 276:60-66, 1997). In total, 395,234 SAGE tags were isolated from regenerating liver (See Table 6). Gene expression patterns of regenerating liver ECs were compared with a combined set of EC libraries derived from all non-proliferating normal organs including resting liver (see FIG. 1D). This comparison revealed 12 genes that were overexpressed in regenerating liver ECs compared to non-angiogenic ECs (Table 9), which were referred to as physiological angiogenesis endothelial markers.

[0279]At least seven of these genes may ...

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Abstract

Methods of inhibiting pathological angiogenesis in a subject are disclosed. In particular examples, the method includes administering a therapeutically effective amount of a composition to a subject wherein the composition includes a specific binding agent that preferentially binds to one or more pathological angiogenesis marker proteins including Vscp, CD276, ETSvg4 (Pea3), CD137(4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, and collagen VIIIα1. In additional examples, methods to deliver a therapeutic agent to a brain or liver endothelial cell are also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 858,068, filed on Nov. 9, 2006 and U.S. Provisional Application No. 60 / 879,457, filed on Jan. 8, 2007, which are both incorporated herein by reference.FIELD[0002]The present disclosure relates to the field of angiogenesis and endothelial cell markers and in particular, to pathological angiogenesis endothelial markers and organ-specific endothelial markers and methods of their uses.BACKGROUND[0003]Inhibition of tumor angiogenesis is an anticancer strategy that has gained widespread support from biologists and clinicians. In 1971, Dr. Judah Folkman introduced the concept of an “angiogenic switch” driving tumor growth and malignant progression. There have since been numerous scientific reports confirming the central concept that tumor growth is angiogenesis-dependent. Angiogenesis can occur under “normal” physiological conditions, such as during growth and development...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/00A61K39/395C12Q1/68G01N33/53C12N5/02A61P35/04
CPCC12Q1/6886A61K39/39558G01N33/6893C12N15/1072A61K45/06A61P35/00A61P35/04C12Q2600/158C12Q2600/16G01N33/574G01N33/57407G01N33/57492G01N33/57496
Inventor ST. CROIX, BRADSEAMAN, STEVEN
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