Prostate cancer and Wnt pathway

Inje universityPaik hospital Busan

Department of urology

DONG IL KANG

Wnt pathway

Int-1 (cellular oncogne) mouse mammary tumor virus induced tumor

Nusse R and Varmus HE 1982 cell

bull Int-1 = wingless (Elucidate through analysis of wingless signalling-drosophila homolog)

Rijsewijk et al 1987 Cell

bull Wnt=Int-1 +Wingless(Wg) Nusse et al1991 cell

bull Wnt protein- large family of cysteine-rich secreted lignads

httpwwwstanfordedugroupnusselabcgi-binwnt

Stanford University Dr Roel Nusse group

httpwwwstanfordedugroupnusselabcgi-binwnt

What is Wnts pathway

bull Wnt proteins1cysteine-rich-secreted ligand glycoproteins2Autocrine or paracrine effects3Organ development tissue patterning cell fate

and proliferation movement4activate at least three distinct pathways

-Canonical (b-catenin-dependent) -Non-canonical -Ca2+ or planar polarity

Regulation of β-catenin levels and translation

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

Wnt pathway

Int-1 (cellular oncogne) mouse mammary tumor virus induced tumor

Nusse R and Varmus HE 1982 cell

bull Int-1 = wingless (Elucidate through analysis of wingless signalling-drosophila homolog)

Rijsewijk et al 1987 Cell

bull Wnt=Int-1 +Wingless(Wg) Nusse et al1991 cell

bull Wnt protein- large family of cysteine-rich secreted lignads

httpwwwstanfordedugroupnusselabcgi-binwnt

Stanford University Dr Roel Nusse group

httpwwwstanfordedugroupnusselabcgi-binwnt

What is Wnts pathway

bull Wnt proteins1cysteine-rich-secreted ligand glycoproteins2Autocrine or paracrine effects3Organ development tissue patterning cell fate

and proliferation movement4activate at least three distinct pathways

-Canonical (b-catenin-dependent) -Non-canonical -Ca2+ or planar polarity

Regulation of β-catenin levels and translation

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

Stanford University Dr Roel Nusse group

httpwwwstanfordedugroupnusselabcgi-binwnt

What is Wnts pathway

bull Wnt proteins1cysteine-rich-secreted ligand glycoproteins2Autocrine or paracrine effects3Organ development tissue patterning cell fate

and proliferation movement4activate at least three distinct pathways

-Canonical (b-catenin-dependent) -Non-canonical -Ca2+ or planar polarity

Regulation of β-catenin levels and translation

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

What is Wnts pathway

bull Wnt proteins1cysteine-rich-secreted ligand glycoproteins2Autocrine or paracrine effects3Organ development tissue patterning cell fate

and proliferation movement4activate at least three distinct pathways

-Canonical (b-catenin-dependent) -Non-canonical -Ca2+ or planar polarity

Regulation of β-catenin levels and translation

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

Regulation of β-catenin levels and translation

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

bull By Wnt1Wnt2Wnt3a Wnt10a

bull Dependent β

-catenin

bull Main protein β

ndashcatenin

①is degradated by GSK3b

②Structural adaptor protein actin+cadherin

Canonical Wnts pathway

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

LNCaP

22RV1

Con

Con

Wnt3A

Wnt3A

AR β-catenin DAPI Merge

Wnt3a and β-catenin by IF

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

Non-canonical Wnts pathway

bull Via Frizzled and Ror1 or Ror2 receptorbull Via G protein control of Ca2+ fluxes and

phosphatidyl inositide metabolismbull Initiate the RhoA JNK(C-jun N-terminla

kinase) calcium signaling pathwaybull Maybe play roles in guiding mesenchymal stem

cell fate bull Wnt4 Wnt5a Wnt11

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

Wnt5a protein activates szlig-catenin signaling depending on receptor

context

PLoS Biol 2006 Apr4(4)e115 Epub 2006 Apr 4 Mikels AJ Nusse R

bull Wnt5a is essential for normal prostate development where its regulates bud outgrowth ductal elongation braching cell polarity and lumenization

Normal prostate gland development and Wnt5a in rats

Huang L et al 2009 Dev Biol

Wnt pathway and prostate cancer

Mutation of β-catenin in prostate cancer

bull Exon 3 of the β-catenin gene CTNNB1rarrsite of phosphoylation of β-catenin rarr stabilization of β-catenin

Voeller et al 1998 cancer res Gerstein et al2002 Genes Chromosomes Cancer

Chesire et al 2000 prostate

bull APC mutation Gerstein et al2002 Genes Chromosomes Cancer

Wnt signalling

Alteration in expression of β- catenin in prostate cancer

Location change of β-catenin increasing in cytoplasm and nuclus

Chesire et al 2002 oncogeneDe la Taille et al 2003 clinical cancer res

Chen et al 2004 Cancer

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Wnt pathway and prostate cancer

Mutation of β-catenin in prostate cancer

bull Exon 3 of the β-catenin gene CTNNB1rarrsite of phosphoylation of β-catenin rarr stabilization of β-catenin

Voeller et al 1998 cancer res Gerstein et al2002 Genes Chromosomes Cancer

Chesire et al 2000 prostate

bull APC mutation Gerstein et al2002 Genes Chromosomes Cancer

Wnt signalling

Alteration in expression of β- catenin in prostate cancer

Location change of β-catenin increasing in cytoplasm and nuclus

Chesire et al 2002 oncogeneDe la Taille et al 2003 clinical cancer res

Chen et al 2004 Cancer

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Mutation of β-catenin in prostate cancer

bull Exon 3 of the β-catenin gene CTNNB1rarrsite of phosphoylation of β-catenin rarr stabilization of β-catenin

Voeller et al 1998 cancer res Gerstein et al2002 Genes Chromosomes Cancer

Chesire et al 2000 prostate

bull APC mutation Gerstein et al2002 Genes Chromosomes Cancer

Wnt signalling

Alteration in expression of β- catenin in prostate cancer

Location change of β-catenin increasing in cytoplasm and nuclus

Chesire et al 2002 oncogeneDe la Taille et al 2003 clinical cancer res

Chen et al 2004 Cancer

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Wnt signalling

Alteration in expression of β- catenin in prostate cancer

Location change of β-catenin increasing in cytoplasm and nuclus

Chesire et al 2002 oncogeneDe la Taille et al 2003 clinical cancer res

Chen et al 2004 Cancer

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Alteration in expression of β- catenin in prostate cancer

Location change of β-catenin increasing in cytoplasm and nuclus

Chesire et al 2002 oncogeneDe la Taille et al 2003 clinical cancer res

Chen et al 2004 Cancer

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Wnt pathway may contribute to progression of prostate cancer to androgen independence

De la Taille et al 2003 clinical cancer resChen et al 2004 Cancer

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Expression of cytosolic β-catenin

Membrane weak and cytosol weak

Membrane moderate and cytosol weak

Membrane strong and cytosol strongA B

C

Cyt

oso

lic

β-ca

teni

nEx

pre

ssio

n

Disease progression

(-) (+)

Preoperative PSA Bone metastasis

p=0001p=0006p=0001

1rsquo

Gleason grade

D E F

ANOVA or studentrsquos t-test Expression Mean (SE)

X2 test p=0001

p=00001

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

β-catenin and androgen receptorbull Nuclear β-catenins are an activator of the androgen

receptor bull β-catenin significantly enhances androgen-stimulated

transcriptional activity by the AR and diminished its antagonist

bull β-cateninTCF-related transciption is inhibited by androgen treatment

rarr β-catenin may link development of androgen insensitivity

Truica CI et al 2000 Cancer ResCulig Z et al 1998 prostate

Chesire DR et al 2002 oncogen

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

The androgen receptor can signal through Wntbeta- Catenin in prostate cancer cells as an adaptation

mechanism to castration levels of androgens

Schweizer L et al 2008 BMC Cell Biiol

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Bisson I et al 2009 Cell res

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Wnts signaling in cancer

Colon cancer prostate cancer β-catenin mutation or

increased cytosolicnuclear β-catenin

Transciption factor c-Myc cell cycle regulatory protein

cyclin D1 uarr

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

What is the role of Wnts and BMPs pathways in bone metastasis

bull The most common site of CaP metastasis is the bone with up

to 84 of patientsdemonstrating skeletal metastases

bull The majority of cancers such as breast and myeloma produce

areas of bone lysis (osteolytic lesions) when they metastasize

to bone

bull Although there is consistently an osteolytic component to CaP

bone metastases they are typically characterized

radiographically by areas of increased bone production (ie

osteoblastic)

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Wnt pathway and bone metastasis

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent

and independent mechanisms

Cancer Res 2008 Jul 1568(14)5785-94

Take home Message

Wnt pathway is the important component of prostate cancer progression and tumorigenesisA variable chemoprevention agents have an

effect on the Wnt β-catenin pathway- folic acid Cyclooxygenase inhibitors NSAIDs- β-catenin-TCFLEF transcription complex inhibitor- APC function mimicking agent

Thank you very much for your attention

• Prostate cancer and Wnt pathway
• Wnt pathway
• Stanford UniversityDr Roel Nusse grouphttpwwwstanfordedugroupnusselabcgi-binwnt
• What is Wnts pathway
• Regulation of β-catenin levels and translation
• Canonical Wnts pathway
• Slide Number 7
• Non-canonical Wnts pathway
• Slide Number 9
• Slide Number 10
• Wnt5a protein activates szlig-catenin signaling depending on receptor context
• Normal prostate gland development and Wnt5a in rats
• Wnt pathway and prostate cancer
• Mutation of β-catenin in prostate cancer
• Wnt signalling
• Alteration in expression of β-catenin in prostate cancer
• Wnt pathway may contribute to progression of prostate cancer to androgen independence
• Expression of cytosolic β-catenin
• β-catenin and androgen receptor
• The androgen receptor can signal through Wntbeta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens
• WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics
• Wnts signaling in cancer
• What is the role of Wnts and BMPs pathways in bone metastasis
• Wnt pathway and bone metastasis
• Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms
• Take home Message
• Thank you very much for your attention

Thank you very much for your attention

• Prostate cancer and Wnt pathway
• Wnt pathway
• Stanford UniversityDr Roel Nusse grouphttpwwwstanfordedugroupnusselabcgi-binwnt
• What is Wnts pathway
• Regulation of β-catenin levels and translation
• Canonical Wnts pathway
• Slide Number 7
• Non-canonical Wnts pathway
• Slide Number 9
• Slide Number 10
• Wnt5a protein activates szlig-catenin signaling depending on receptor context
• Normal prostate gland development and Wnt5a in rats
• Wnt pathway and prostate cancer
• Mutation of β-catenin in prostate cancer
• Wnt signalling
• Alteration in expression of β-catenin in prostate cancer
• Wnt pathway may contribute to progression of prostate cancer to androgen independence
• Expression of cytosolic β-catenin
• β-catenin and androgen receptor
• The androgen receptor can signal through Wntbeta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens
• WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics
• Wnts signaling in cancer
• What is the role of Wnts and BMPs pathways in bone metastasis
• Wnt pathway and bone metastasis
• Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms
• Take home Message
• Thank you very much for your attention