WO2008071987A1 - Module de cellule souche de prostate - Google Patents

Module de cellule souche de prostate Download PDF

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Publication number
WO2008071987A1
WO2008071987A1 PCT/GB2007/004806 GB2007004806W WO2008071987A1 WO 2008071987 A1 WO2008071987 A1 WO 2008071987A1 GB 2007004806 W GB2007004806 W GB 2007004806W WO 2008071987 A1 WO2008071987 A1 WO 2008071987A1
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prostate
cell
cells
cell culture
prostate stem
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PCT/GB2007/004806
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English (en)
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Shona Lang
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The University Of York
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0681—Cells of the genital tract; Non-germinal cells from gonads
    • C12N5/0683—Cells of the male genital tract, e.g. prostate, epididymis; Non-germinal cells from testis, e.g. Leydig cells, Sertoli cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0693—Tumour cells; Cancer cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2503/00—Use of cells in diagnostics
    • C12N2503/02—Drug screening
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/03—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from non-embryonic pluripotent stem cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/50—Proteins
    • C12N2533/52—Fibronectin; Laminin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/50—Proteins
    • C12N2533/54—Collagen; Gelatin

Definitions

  • the invention relates to a method for the formation of prostate acini from prostate stem cells and uses of the acini so formed in drug screening.
  • the prostate gland is the major accessory organ of the male reproductive tract, and is the most common site of neoplastic disorders in men.
  • the two main pathologies of the gland are: (i) benign prostatic hyperplasia, which is a non-malignant condition that is common with age and (ii) carcinoma, which is the second most common cause of death in European men, after lung cancer and is increasingly prevalent in our ageing Western Society.
  • Symptoms include, blood in the semen or the urine, frequent pain or stiffness in the lower back, hips or upper thigh.
  • Prostate tumours may be primary (i.e. located in the organ of origin) or secondary (i.e. tumours which form in other organs due to the ability of cancerous cells to move and invade other tissues via the circulatory system).
  • Prostate cancer can be relatively harmless or extremely aggressive. Some prostate tumours are slow growing and cause few clinical symptoms. Aggressive prostate tumours spread rapidly to the lymph nodes and other organs, especially bone. It is known that the growth of prostate cancer can be inhibited by blocking the supply of male hormones such as testosterone. However, prostate cancers eventually develop and become independent of male sex hormones (i.e. they become androgen-independent prostate cancer cells). These cells are linked with aggressive, malignant prostate cancer. All male mammals have a prostate gland but only humans and dogs are known to naturally develop prostate cancer.
  • Metastatic prostate cancers predominantly move to the bone and are treated by reducing the production of androgens by blocking androgen production by the adrenal glands and testis. This treatment is only effective for a short period of time as the metastatic lesions become androgen independent and grow uncontrollably. The presence of androgen independent prostate cancer cells means that this treatment regime is no longer effective and further intervention is required to control the progress of the disease. A similar response is seen to chemotherapeutic and radiotherapy treatments. As a result, metastatic prostate cancer remains an incurable disease by current treatment strategies. There is therefore a continual need to identify new therapeutic targets to provide new treatments for prostate cancer and to provide models for testing the efficacy of agents against the progression of prostate cancer.
  • acini are morphologically and physiologically similar to native acini found in the prostate gland and have utility in studying prostate biology.
  • the acini formed by these methods also have utility with respect to drug screening and in particular, the identification of anti-cancer agents effective in inhibiting prostate cancer cell proliferation and/or metastatic movement of transformed prostate cells.
  • WO03/014334 we describe a method for the formation of prostate acini from prostate epithelial cells.
  • the cell culture conditions described in WO03/014334 relates to a combination of cell culture medium and a ratio of the hormones oestrogen and dihydrotestosterone and the culturing of epithelial cells on a cell culture support that comprises collagen in the form of MatrigefTM.
  • WO2005/089043 the content of which is incorporated by reference, we describe a population of prostate stem cells that express CD133 antigen, a haematopoietic stem cell marker.
  • CD133 cells are restricted to the Ot 2 P 1 111 population (the receptor for type I collagen) and are located in the basal layer, often at the base of a budding region or branching point (Fig. 1A).
  • ⁇ 2 ⁇ i hl /CD133 + cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential (Fig. 1B) and can reconstitute prostatic-like acini in immunocompromised male nude mice (Fig. 1C).
  • Fig. 1B in vitro proliferative potential
  • Fig. 1C immunocompromised male nude mice
  • the present disclosure relates to conditions that enable the in vitro formation of prostate acini from a population of prostate stem cells, in particular cancerous prostate stem cells.
  • the conditions that allow the formation of prostate acini that start with CD133 positive prostate stem cells are very different when compared to prostate epithelial cells as described in WO03/014334.
  • an in vitro method for the formation of prostate acini from prostate stem cells comprising: i) providing a cell culture vessel comprising at least one prostate stem cell that expresses CD133 antigen; cell culture medium optionally including a laminin based cell support and cell culture conditions that substantially prevents said cell attaching to the cell culture surface of the cell culture vessel thereby promoting the aggregation of prostate stem cells in suspension; ii) contacting said cell aggregate with a laminin based cell support and a prostate stromal fraction; and iii) providing cell culture conditions that allow the formation of a prostate acinus from said CD133 antigen expressing prostate stem cell.
  • said cell culture vessel in (i) includes a collagen IV/ laminin based cell support.
  • the cell culture surface of the cell culture vessel is modified to inhibit or prevent the prostate stem cells attaching and proliferating.
  • said cell culture surface is coated with a polymeric substance that prevents the attachment of prostate stem cells, for example poly(2- hydroxyethyl methacrylate.
  • said prostate stromal fraction is provided in a separate vessel but in liquid contact with the prostate stem cells which allows the cells contained in the stromal fraction to proliferate but prevents cell contact with the prostate stem cells contained in the cell culture vessel.
  • said prostate stem cell expresses high levels of ⁇ 2 ⁇ i integrin.
  • said prostate stem cell expresses human epithelial antigen.
  • said cell expresses CD44 antigen.
  • said prostate stem cell expresses CD133 antigen, high levels of ⁇ 2 ⁇ i integrin, human epithelial antigen and CD44 antigen.
  • said prostate stem cell is isolated from a primary source of prostate tissue.
  • said prostate stem cell is a cancerous prostate stem cell.
  • said cancerous prostate stem cell is isolated from a primary source of malignant prostate tissue.
  • said cancerous prostate stem cell is isolated from primary metastatic lymph node tissue.
  • said collagen based matrix comprises collagen IV/ laminin.
  • said collagen based cell support is Matrigel R TM.
  • said cell culture medium supplement includes fibronectin.
  • said prostate-like acinus comprises genetically engineered prostate cells.
  • pro-drug activating genes may be transfected into prostatic cells to monitor the efficacy of pro-drugs as cytotoxic agents.
  • a pro-drug activating gene refers to a gene the expression of which results in the production of protein capable of converting a non- therapeutic compound into a therapeutic compound, which renders the cell susceptible to killing by external factors or causes a toxic condition in the cell.
  • cytosine deaminase converts 5-fluorocytosine to 5-fluorouracil, a potent antitumor agent.
  • the lysis of the tumor cell provides a localized burst of cytosine deaminase capable of converting 5FC to 5FU at the localized point of the tumour resulting in the killing of many surrounding tumour cells. This results in the killing of a large number of tumour cells without the necessity of infecting these cells with a vector (the so-called "bystander effect").
  • TK thymidine kinase
  • US5, 631 ,236 and US 5,601 ,8128 thymidine kinase
  • tumour suppressor gene refers to a nucleotide sequence, the expression of which in a target cell is capable of suppressing the cancerous phenotype and/or inducing apoptosis.
  • said acini is analysed for the expression of prostate specific gene expression comprising the steps of:
  • said method includes the additional steps of: i) collating the signal(s) generated by the binding of said nucleic acid to said binding partner; ii) converting the collated signal(s) into a data analysable form; and optionally; iii) providing an output for the analysed data.
  • said acinus is processed for the preparation of a cDNA library comprising prostate specific gene expression products comprising the steps: i) providing a preparation comprising at least one acinus according to the invention; ii) extracting nucleic acid from said preparation; iii) preparing a cDNA from ribonucleic acid contained in said extracted nucleic acid; and iv) ligating cDNA formed in (iii) into a vector.
  • said vector is a phage based vector.
  • a method to identify agents capable of inhibiting the proliferation of cancerous prostatic cells comprising: i) adding at least one agent to be tested to said cell culture vessel; and ii) monitoring the anti-proliferative activity of the agent with respect to the cells comprising the cancerous acinus.
  • a method to identify agents capable of inhibiting the motility of cancerous prostatic cells comprising: i) adding at least one agent to be tested; and ii) monitoring the motility of cells comprising the cancerous acinus.
  • Prostate stem cells/prostate cancer stem cells are typically characterised by specific phenotypic characteristics. For example, cells with stem cell potential are able to divide in culture in an undifferentiated state for multiple passages; able to form all the cell-types found in prostate tissue; and express gene markers of prostate stem cells and/or differentiated prostate cells. These characteristics are merely meant to be illustrative of prostate stem cells and not meant to be restrictive.
  • Cell culture vessel is defined as any means suitable to contain the above described cell culture. Typicallly examples of such vessel is a round bottomed mutilwell culture dish (e.g. 24, 96).
  • said agent is a chemotherapeutic agent.
  • said agent is a polypeptide effective in the inhibition of proliferation or metastasis of prostate cancer; preferably said agent is an antibody, or active binding fragment thereof.
  • said antibody is monoclonal antibody.
  • said monoclonal antibody is a humanised or chimeric antibody.
  • a chimeric antibody is produced by recombinant methods to contain the variable region of an antibody with an invariant or constant region of a human antibody.
  • a humanised antibody is produced by recombinant methods to combine the complementarity determining regions (CDRs) of an antibody with both the constant (C) regions and the framework regions from the variable (V) regions of a human antibody.
  • CDRs complementarity determining regions
  • Chimeric antibodies are recombinant antibodies in which all of the V-regions of a mouse or rat antibody are combined with human antibody C-regions.
  • Humanised antibodies are recombinant hybrid antibodies that fuse the complimentarity determining regions from a rodent antibody V-region with the framework regions from the human antibody V- regions. The C-regions from the human antibody are also used.
  • the complimentarity determining regions (CDRs) are the regions within the N-terminal domain of both the heavy and light chain of the antibody to where the majority of the variation of the V- region is restricted. These regions form loops at the surface of the antibody molecule. These loops provide the binding surface between the antibody and antigen.
  • Antibodies from non-human animals provoke an immune response to the foreign antibody and its removal from the circulation.
  • Both chimeric and humanised antibodies have reduced antigenicity when injected to a human subject because there is a reduced amount of rodent (i.e. foreign) antibody within the recombinant hybrid antibody, while the human antibody regions do not elicit an immune response. This results in a weaker immune response and a decrease in the clearance of the antibody. This is clearly desirable when using therapeutic antibodies in the treatment of human diseases.
  • Humanised antibodies are designed to have less "foreign" antibody regions and are therefore thought to be less immunogenic than chimeric antibodies.
  • scFvs single chain antibody variable region fragments
  • FIG. 1 Verification of CD133 as a stem cell marker of prostatic epithelia: 1A: A paraffin section of prostatic acini labelled with the nuclear stain DAPI (Blue) and anti- CD133 directly conjugated to PE (Red). 1B: Basal cells with the phenotype ⁇ 2 ⁇ i hl /CD133 + have a higher colony forming efficiency (CFE) than ⁇ 2 ⁇ i' 0W /CD133 " . (CFE) was calculated as the number of colonies formed per number of selected cells x100%. CFEs are expressed as the ratio of the control CFE. Results show means ⁇ s.e.m of four experiments. 1C.
  • Xenografts of prostate acini formed by transplantation of ⁇ 2 ⁇ i W /CD133 + basal cells stained with (A) Haematoxylin and Eosin, (B) 34 ⁇ E12, (C) anti-K18, (D) anti-PAP (E) Anti-androgen receptor. Bar 40 ⁇ m;
  • Figure 2 illustrates one embodiment of the invention to form prostate acini from CD133 antigen specific stem cells
  • Figure 3 illustrates an alternative embodiment of the invention to form prostate acini from CD133 antigen specific stem cells.
  • the medium was also supplemented with 2 ng/mL of leukemia inhibitory factor (LIF; Sigma, Poole, United Kingdom), 2 ng/mL of stem cell factor (Sigma), and 100 ng/mL of cholera toxin (Sigma). Cultures were also derived from two lymph node metastasis of the prostate but initially from an unselected epithelial population. However, after expansion in culture CD44/a2h1hi/CD133+ were isolated and cultures were derived.
  • LIF leukemia inhibitory factor
  • stem cell factor Sigma
  • cholera toxin Sigma
  • CD44+/a2h1hi/CD133+ stem cells
  • CD44+/a2h1hi/CD133 transit amplifying population
  • CD44+/a2h1low committed basal population
  • STO mouse embryonic fibroblasts
  • Anchorage-independent growth was also assessed in methylcellulose (Miltenyi Biotec Ltd., Bisley, Surrey, United Kingdom). Briefly, the above phenotypes were placed in complete methylcellulose (supplemented with EGF, bovine pituitary extract, stem cell factor, LIF, and cholera toxin at the concentrations used for complete keratinocyte serum-free medium) and the number of surviving cells was counted after 28 days. The results were subjected to a paired t test to determine statistical significance. lmmunofluorescent staining of CD44+/A2B1 hi/CD133+ cells.
  • CD44+/ a2hhi1 /CD133+ cells were selected directly from disaggregated tumor tissue or cultured cells from tumours before processing for dual-color imaging under confocal microscopy by fixation in ice-cold methanol for 20 minutes and permeabilization in 0.4% Triton X-100 (Sigma) containing 0.3% normal goat serum (NGS) for 10 minutes.
  • Appropriate positive control cells were stained in parallel for each antibody used for CD133+ cell phenotyping. After washing (3. TBS), cells were further probed with FITC-tagged secondary antibody. Cells were mounted in the antiphotobleaching medium Vectashield containing 4V,6-diamidino-2-phenylindole (DAPI; Vector Laboratories).
  • DAPI Vectashield containing 4V,6-diamidino-2-phenylindole
  • D8S560, D8S592, and D16S422) were used in a PCR as previously described (14).
  • Touchdown PCR to take account of varying base pair composition was used (10 minutes at 94jC; followed by 16 touchdown cycles of 94JC/45 seconds, 60-52JC/45 seconds, 72JC/30 seconds; then 16 cycles of 94JC/45 seconds; 52JC/45 seconds, 72JC/30 seconds; and finally 72JC/7 minutes).
  • Analysis of the labeled fragments was accomplished on a Beckman Coulter CEQ8000 and proprietary CEQ fragment analysis software to accurately size and quantify alleles.
  • CD133+ cells are plated per well of a 96 well plates (round bottomed, coated with 0.125mg polyhema). These are cultured in stem cell media supplemented with 4%

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Abstract

La présente invention concerne un procédé permettant la formation d'acini prostatiques provenant de cellules souches de prostate.
PCT/GB2007/004806 2006-12-15 2007-12-14 Module de cellule souche de prostate WO2008071987A1 (fr)

Applications Claiming Priority (2)

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GB0625041.9 2006-12-15
GB0625041A GB0625041D0 (en) 2006-12-15 2006-12-15 Prostate stem cell model

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WO2008071987A1 true WO2008071987A1 (fr) 2008-06-19

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003014334A1 (fr) * 2001-08-09 2003-02-20 Procure Therapeutics Limited Procede de culture cellulaire permettant d'obtenir des acini de type prostatique
WO2005089043A2 (fr) * 2004-03-19 2005-09-29 Procure Therapeutics Limited Cellules souches de la prostate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003014334A1 (fr) * 2001-08-09 2003-02-20 Procure Therapeutics Limited Procede de culture cellulaire permettant d'obtenir des acini de type prostatique
WO2005089043A2 (fr) * 2004-03-19 2005-09-29 Procure Therapeutics Limited Cellules souches de la prostate

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Biochemikalien und Reagenzien für die Life Science Forschung", 1998, SIGMA ALDRICH COMPANY, XP002471772 *
DAVID L HUDSON: "Prostate epithelial stem cell culture", CYTOTECHNOLOGY, KLUWER ACADEMIC PUBLISHERS, DO, vol. 41, no. 2-3, 1 March 2003 (2003-03-01), pages 189 - 196, XP019236779, ISSN: 1573-0778 *
IVASCU A. AND KUBBIES M.: "Rapid generation of single-tumor spheroids for high-throughput cell function and toxicity analysis", JOURNAL OF BIOMOLECULAR SCREENING, vol. 11, no. 8, 1 December 2006 (2006-12-01), pages 922 - 932, XP009096939 *
TRAN NHAN L ET AL: "N-cadherin expression in human prostate carcinoma cell lines: An epithelial-mesenchymal transformation mediating adhesion with stromal cells", AMERICAN JOURNAL OF PATHOLOGY, vol. 155, no. 3, September 1999 (1999-09-01), pages 787 - 798, XP002471771, ISSN: 0002-9440 *

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