ALDH1 As A Cancer Stem Cell Marker

a stem cell marker and aldehyde dehydrogenase technology, applied in the field of stem cell cancer markers, aldehyde dehydrogenase 1 (aldh1), can solve the problems of increasing the quality of life, prolonging the disease-free state and overall survival rate, and preventing cancer

Inactive Publication Date: 2008-08-07
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0030]In some embodiments, the present invention provides methods for determining the effect of a test compound on a solid tumor stem cell, comprising the steps of: (a) obtaining an enriched population of solid tumor stem cells, wherein; (i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem ce

Problems solved by technology

Although its mortality has not increased along with its incidence, due to earlier diagnosis and improved treatment, it is still one of the predominant causes of death in middle-aged women.
However, the currently available treatment options often prolong the disease-free state and overall survival rate, as well as increase the quality of the life.
The morphologic appearance of the tumor can also be assessed but because tumors with similar histopathologic appearance can exhibit significant clinical variability, this approach has serious limitations.
Yet these analyses, though useful, are only partially predictive of the clinical behavior of breast tumors, and there is much phenotypic diversity present in breast cancers that current diagnostic tools fail to detect.
Furthermore, although current therapies can often prolong the disease-free state and overall survival when used on high-risk patients, they are limited by their lack of specificity and the emergence of treatment-resistant cancer cells.
Becaus

Method used

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  • ALDH1 As A Cancer Stem Cell Marker
  • ALDH1 As A Cancer Stem Cell Marker
  • ALDH1 As A Cancer Stem Cell Marker

Examples

Experimental program
Comparison scheme
Effect test

example 1

ALDH Positive Population Isolated from the Normal Mammary Epithelium Has Stem Cell Like Characteristics

[0112]The ALDEFLUOR test was utilized to assess the presence and size of the ALDH+ population in normal human breast samples. Single cell suspensions of normal mammary epithelial cells were obtained by mechanical and enzymatic digestion of mammoplasty samples, as previously described (Dontu et al., supra). Analysis of samples from 8 different patients showed an average of 6% ALDH+ population, in normal mammary epithelial cells (FIG. 1).

[0113]The clonegencity of this population was analyzed in suspension culture (non-adherent mammospheres) and on collagen substratum (conditions that promote differentiation). Only the ALDH positive population was capable of generating mammospheres in suspension culture, whereas the ALDH negative population failed to grow in anchorage independent conditions (FIG. 2A). Previously published data supports the idea that the mammary epithelial cell populat...

example 2

Tumorigenicity of the ALDH Positive Cells Isolated from Human Breast Cancers

[0115]The same Adefluor test was used to investigate the representation of the ALDH+ population in breast cancer cells. Two human breast cancers (MC1 an ER−PR−Her2-tumor and UM2, an ER+PR+Her2-tumor) were analyzed orthotopically xenotransplanted in NOD / scid mice (these cells were not grown in vitro). The ALDH+ population was present and represented approximately 5% (MC1) and 8% (UM2) of the total cell population. The tumorigenicity of the ALDH+ population sorted from MC1 was tested in serial passages, using limiting dilutions of cells (50,000 cells, 5000 cells and 500 cells). Three passages were performed, and in all three only the ALDH+ cells formed tumors, even when implanted in low numbers. As shown in FIG. 3C, size and latency of tumor formation correlated with the number of ALDH+ cells injected. Remarkably, ALDH+ cells were capable to generate a tumor in only a month, from 500 cells injected. ALDH− cell...

example 3

In Situ Immunostaining Using ALDH1 Antibody

[0117]The early studies showing a correlation between ALDH expression and hematopoietic stem cells used fixed cells and staining with ALDH 1 antibody (Kastan et al., Blood, 75:1947-1950, 1990, herein incorporated by reference). ALDH being a cytosolic enzyme, this method is not useful for studies in which functional properties of the ALDH positive cells need to be assessed. The ALDEFLUOR kit was developed to address this problem. Viable cells that express ALDH 1 can be isolated by flow cytometry, using fluorescent aldehyde substrates that freely diffuse across cell membranes. Using this enzymatic assay and flow cytometry activated cell sorting (FACS), ALDH+ cells can be isolated and cultured or used in in vivo experiments.

[0118]However, the in situ detection of normal or cancer stem cells, is an important step forward for the application in of cancer stem concepts to clinical practice, by enabling the use of stem cell markers in roution exam...

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Abstract

The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides a novel stem cell cancer marker, ALDH1, useful for the diagnosis, characterization, and treatment of solid tumor stem cells.

Description

[0001]The present application claims priority to U.S. Provisional Application Ser. No. 60 / 846,648 filed Sep. 22, 2006, which is herein incorporated by reference.[0002]This invention was made with government support under Grant No. R01-CA010860 awarded by the National Institutes of Health. The Government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides a novel stem cell cancer marker, aldehyde dehydrogenase 1 (ALDH1), useful for the diagnosis, characterization, and treatment of solid tumor stem cells.BACKGROUND OF THE INVENTION[0004]Breast cancer is the most common female malignancy in most industrialized countries, as it is estimated to affect about 10% of the female population during their lifespan. Although its mortality has not increased along with its incidence, due to earlier diagnosis and improved treatment,...

Claims

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Application Information

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IPC IPC(8): G01N33/53C12N5/00
CPCC12N5/0693G01N2333/90203G01N33/57419G01N33/57415
Inventor WICHA, MAX S.DONTU, GABRIELAGINESTIER, CHRISTOPHECHARAFE-JAUFFRET, EMMANUELLELIU, SULING
Owner RGT UNIV OF MICHIGAN
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