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Methods and uses thereof of prosaposin

a tumor and prosthesis technology, applied in the field of tumor metastasis treatment, can solve the problems of not meeting the requirements of tumor establishment and growth at the metastatic site, and the regulation of thrombospondin (tsp-1), one of the most potent endogenous anti-angiogenic proteins, in the tumor-associated stroma, etc., to facilitate recombinant protein expression and purification, and improve serum half-life in vivo.

Inactive Publication Date: 2010-06-10
CHILDRENS MEDICAL CENT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In one embodiment, the Psap protein is saposin A (SEQ. ID. No. 13) or smaller functional fragments and variants thereof. In another embodiment, the smaller functional fragment or variant of saposin A is at least 10 amino acid residues and is capable of activating p53 and inducing Tsp-1 expression. In yet another embodiment, the smaller functional fragment or variant of saposin A is fused to other protein or portions thereof, or conjugated with a polymer, wherein the fragment or variant can still activate p53 and induce Tsp-1 expression. For examples, the other protein or portions thereof or polymer can be transferrin, Fc portion of IgG, albumin, and PEG, for the purpose of improving serum half-life in vivo. Other examples include to thioredoxin and six histidine tag for facilitating recombinant protein expression and purification; and to angiotensin and endostatin for improving anti-angiogenic activity.

Problems solved by technology

These studies, though yielding key insights into two critical steps of tumor metastasis, namely intravasation and homing, did not address the requirements for tumor establishment and growth at the metastatic site.
However, the regulation of Thrombospondin (Tsp-1), one of the most potent endogenous anti-angiogenic proteins, in the tumor-associated stroma have not been as well studied (Kalas et al., 2005).

Method used

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  • Methods and uses thereof of prosaposin
  • Methods and uses thereof of prosaposin
  • Methods and uses thereof of prosaposin

Examples

Experimental program
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Effect test

example 1

Tsp-1 Expression is Inversely Related to Metastatic Potential

[0383]The initial step of metastasis is dependent on access to the vasculature or lymphatic system. Metastatic human tumors may differ in the relative of expression of pro- and anti-angiogenic proteins compared to non-metastatic tumors. Thus, the level of VEGF secretion by the weakly metastatic prostate cancer cell line PC3 and a metastatic derivative PC3M-LN4 as well as by the breast cancer cell line MDA-MB-231 and a bone-specific metastatic derivative MDA-MET were measured. PC3M-LN4 cells have been documented to metastasize to multiple organs, including lymph node, liver, lung and bone, while MDA-MET was derived to metastasize only to bone via intra-cardiac injection (Bendre et al., 2002; Pettaway et al., 1996).

[0384]Highly metastatic PC3M-LN4 cells and MDA-MET cells secreted lower levels of VEGF than their parental counterparts, as measured by ELISA (FIG. 1A). Even under hypoxic conditions (1% O2), the relative levels r...

example 2

Myc Expression is Directly Related to Metastatic Potential

[0386]It has been demonstrated that c-myc is often amplified or overexpressed in several types of human cancer, including prostate and breast cancer (Escot et al., 1986; Nag and Smith, 1989). Furthermore, c-Myc represses the expression of Tsp-1 (Janz et al., 2000; Ngo et al., 2000; Tikhonenko et al., 1996; Watnick et al., 2003). Therefore, the levels of c-Myc was analyzed to determine whether the levels of c-Myc increase as tumors progress to the metastatic phenotype. The levels of c-Myc increase with the metastatic potential of both prostate and breast cancer cells were examined. Protein expression of c-Myc was significantly increased in the highly metastatic PC3M-LN4 and MDA-MET cells as compared to the parental PC3 and MDA-MB-231 cells (FIG. 1B). Furthermore, levels of phosphorylated c-Myc, which have been shown to be directly involved in Tsp-1 repression (Watnick et al., 2003), were also significantly increased in the met...

example 3

Expression of Tsp-1 in Primary Tumors

[0387]In order to determine whether levels of Tsp-1 observed in in vitro culture conditions were representative of their expression levels in vivo, 2×106 PC3 and their metastatic derivatives, PC3M-LN4 cells, were injected orthotopically into the prostate glands of SCID mice. Five weeks after injection the tumors and surrounding tissue were analyzed for Tsp-1 expression via western blot analysis and immunohistochemistry. The prostate tumors formed by both PC3 and PC3M-LN4 cells were histologically characterized by significant nuclear atypia and a diffuse infiltrating growth pattern, i.e. poorly differentiated, often surrounding benign prostate glands. Strong Tsp-1 staining was observed in fibrous stroma surrounding the invading tumor cells in 14 out of 17 PC3 tumors (FIG. 1F) but in only one out of 16 PC3M-LN4 prostate tumors (FIG. 1F). Conversely, undetectable Tsp-1 staining was observed in the fibrous stroma surrounding the remaining tumors (3 / 1...

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Abstract

The invention relates to methods for treating of tumor metastasis, methods for preventing, inhibiting, and predicting tumor recurrence and tumor metastasis, and methods of preventing cancer development for one at risk of developing cancer, for one diagnosed with a benign cancer, and / or for one diagnosed with malignant cancer. The invention also relates to methods of treating angiogenesis-dependent diseases and disorders. In addition, the invention provides: (1) a method for screening for tumor / cancer derived angiogenesis and metastasis factors; (2) a method for screening for compounds that inhibit angiogenesis and metastasis; (3) a method for screening for compounds that promote anti-angiogenesis and anti-metastasis activities; (4) a method for cancer prognosis evaluation; (5) a method for predicting the tissue specificity of a metastatic cancer; (6) a method for determining likelihood of metastasis; and (7) a method for cancer prognosis evaluation by the surveillance of metastasis development.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of the International Application Serial No. PCT / US2008 / 67899, filed on Jun. 23, 2008, which claims benefit under 35 U.S.C. §119(e) of the U.S. provisional application No. 60 / 936,792, filed Jun. 22, 2007, the contents of both of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to methods for treating of tumor metastasis, as well as methods for preventing, inhibiting, and predicting tumor metastasis. The invention further relates to treating angiogenesis-dependent diseases and disorders, screening methods for tumor cell derived anti-angiogenic factors and methods for cancer prognosis evaluation.BACKGROUND OF THE INVENTION[0003]The spread of cancer cells from a primary tumor site to distant organs is known as metastasis. The progression of human cancer to metastatic disease is the major contributing factor to its lethality. Meta...

Claims

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Application Information

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IPC IPC(8): A61K38/17C12Q1/68C07K14/00
CPCC07K14/475A61K38/00A61K45/06A61K38/1709G01N33/574G01N2800/56A61K48/00A61P17/06A61P25/28A61P27/02A61P27/06A61P29/00A61P3/04A61P35/00A61P35/04A61K2300/00
Inventor WATNICK, RANDOLPH
Owner CHILDRENS MEDICAL CENT CORP
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