muc1 is associated with diverse cellular functions in normal epithelial cells muc1 (mucin 1) plays a...

MUC1 Is Associated With DiverseCellular Functions in Normal Epithelial Cells

MUC1 (Mucin 1) Plays a Central RoleIn Cellular Functions of Both NormalEpithelial Cells and Cancer Cells

Role of MUC1 in the Growth, Proliferation and Survivals of Cancer Cells

MUC1 Is a Scientifically Valid Target for Mounting Immune Responses

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© 2013 EMD Serono. All rights reserved.© 2013 EMD Serono. All rights reserved.

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What Role Does MUC1 Play in the Growth, Proliferation and Survival of Cancer Cells?





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What Is the Role of MUC1 inNormal Epithelial Cells?

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What Role May MUC1 Play in the Growth, Proliferation and Survival of Cancer Cells?

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Why Is MUC1 Considered aScientifically Valid Target forCancer Immunotherapy?

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MUC1 Plays a Central Role in Cellular Functions in Epithelial Cells and Cancer Cells

Normally glycosylated MUC1

MUC1 is heavily glycosylatedand expressed on the apical

surfaceof secretory epithelial cells1,2

Cancer-associated MUC1Cancer-associated MUC1 is underglycosylatedand overexpressed on cancer cells1-4

1. Ho SB, et al. 1993;53:641-651. 2. Kufe DW. 2009;9(12):874-885. 3. Hollingsworth MA, et al. 2004;4:45-60. 4. Singh PK, et al. 2006;16:467-476.

© 2013 EMD Serono. All rights reserved.


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MUC Is Overexpressed in Many Cancers

1. Zhong XY, et al. 1993;139:281-286. 2. Data on file. EMD Serono, Inc. 3. Rakha EA, et al. 2005;18:1295-1304. 4. Langner C, et al. 2004;17:180-188. 5. Chauhan SC, et al. 2006;19:1386-1394. 6. Croce MV, et al. 2001;7:284-291. 7. Baldus SE, et al. 2002;40:440-449. 8. Qu CF, et al. 2004;91:2086-2093. 9. DeNardo SJ, et al. 2005;11:7187s-7194s. 10. Utsunomiya T, et al. 1998;4:2605-2614. 11. Saad RS, et al. 2005;32:156-159. 12. Cloosen S, et al. 2006;135:513-516. 13. Kijima H, et al. 2001;21:1285-1289.



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What Is MUC1?

• MUC1 is a large transmembrane glycoprotein found on the apical surface of most secretory epithelial cells

1. Ho SB, et al. 1993;53:641-651.



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What Is the Structure of MUC1?

• MUC1 is comprised of three domains:1-3

– Entracellular domain– Transmembrane domain– Cytoplasmic domain (or tail)

• The extra cellular domain of MUC1 is characterized by many tandem repeat peptides that are extensively glycosylated1-3

1. Ho SB, et al. 1993;53:641-651. 2. Kufe DW. 2009;9(12):874-885. 3. Hollingsworth MA, et al. 2004;4:45-60.

Extracellulardomain

Transmembranedomain

Intracellulardomain



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MUC1 Protects Normal Epithelial Cells as Part of theInnate Immune System

• A central role of MUC1 is to maintain the integrity of the epithelial barrier1

• Extracellular MUC1 forms a protective layer on the apical epithelial cell surface that:1-3

– Provides lubrication– Acts as physical barrier against

pathogens and toxins

1. Hollingsworth MA, et al. Nature Rev Cancer. 2004;4:45-60. 2. Ho SB, et al. Cancer Res. 1993;53:641-651. 3. Kufe DW. Nat Rev Cancer. 2009;9(12):874-885.


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MUC1 Is Involved in Intracellular Signaling Pathways Which Regulate Epithelial Cell Growth, Proliferation and Survival

• The extracellular domain of MUC1 is a sensor of the external environment through ligand binding and as a consequence of changes in biochemical conditions outside the cell1,2

• Signals are transmitted by conformational changes mediated by the extracellular domain to the intracellular domain1-3

• The intracellular domain in turn activates several intracellular signaling pathways that promote the growth, proliferation and survival of normal epithelial cells1-

31. Hollingsworth MA, et al. Nature Rev Cancer. 2004;4:45-60. 2. Ho SB, et al. Cancer Res. 1993;53:641-651. 3. Kufe DW. Nat Rev Cancer. 2009;9(12):874-885.

Key extracellular molecules interacting with MUC1:• ICAM-1• galectin-3• EGFR• Mesothelin


Key intracellular pathwaysactivated by MUC1

PI3K/AKT/mTOR

IKKB/NF-kB

β-catenin/Wnt

RAS/RAF/MEK/MAPK (ERK 1/2)


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Role of MUC1 in the Growth, Proliferation and Survival of Cancer Cells

Cancer-associated MUC1Cancer-associated MUC1 is underglycosylatedand overexpressed on cancer cells1-4

1. Ho SB, et al. 1993;53:641-651. 2. Kufe DW. 2009;9(12):874-885. 3. Hollingsworth MA, et al. 2004;4:45-60. 4. Singh PK, et al. 2006;16:467-476.

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Cancer-associated MUC1 Promtotes the Growth, Proliferations and Survival of Cancer Cells

• Malignant transformation leads to:1,2

– Irreversible loss of epithelial cell polarity

– Aberrant expression of MUC1 over the entire cell surface

– Over expression and underglycosylation of MUC1

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1. Hollingsworth MA, et al. 2004;4:45-60. 2. Singh PK, et al. 2006;16:467-476.





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Cancer-associated MUC1 Promotes the Growth, Proliferation and Survival of Cancer Cells

• Aberrant distribution and overexpression of cancer-associated MUC1 activate both cell surface molecules and intracellular signaling pathways which promote the growth, proliferation and survival of cancer cells1-4

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1. Hollingsworth MA, et al. 2004;4:45-60. 2. Singh PK, et al. 2006;16:467-476. 3. Pochampalli MR, et al. 2007;26:1693-1701. 4. Bafna S, et al. 2010;29:2893-2904.





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Cancer-associated MUC1 Is Underglycosylated Compared to Glycosylated on Normal Epithelial Cells

• Cancer-associated MUC1 is underglycosylated compared with MUC1 expressed on normal epithelial cells1

– Both the length and number of carbohydrate chains are reduced1,2

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Abnormalcarbohydratechain

Cancer-associated MUC1Normally glycosylated MUC1

Core peptide

Normal carbohydrate

chain

1. Ho SB, et al. 1993;53:641-651. 2. Taylor-Papadimitriou J, et al. 1994;12(6):227-233.





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Cancer-associated MUC1 Is a Scientfically Valid Target for Immune Responses Against Cancers


PREVHOME NEXT 1. Hollingsworth MA, et al. 2004;4:45-60. 2. Singh PK, et al. 2006;16:467-476. 3. Pochampalli MR, et al. 2007;26:1693-1701. 4. Bafna S, et al. 2010;29:2893-2904.

MUC1-boundHLA class I molecule

Cancer-associated MUC1





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Dense Glycosylation of MUC1 Inhibits Antigen Processing by Normal Epithelial Cells

• In normal epithelial cells, the dense glycosylation and long carbohydrate chain of MUC1 interfere with antigen processing and results in a compromised presentation of MUC1 peptides bound to human leukocyte antigen (HLA) class I molecules1,2


PREVHOME NEXT 1. Werdelin O, et al. 2002;99(15):9611-9613. 2. Karsten U, et al. 2004;14(8):681-692.

Epthielial cell

Normally glycosylated MUC1HLA class I molecule

HLA complex transported via Golgi to cell surface

Peptides are combined With HLA moleculesInside the ER

Processed peptides are transportedInto the ER

Endoplasmic reticulum (ER)

Normally glycosylated MUC1





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Underglycosylation of Cancer-associated MUC1 Facilitates Antigen Processing by CancerCells

• In cancer cells, the underglycosylated cancer-associated MUC1 is more efficiently processed leading to a much larger repertoire of MUC1-bound HLA class I molecules on cancer cells 3,5


PREVHOME NEXT 3. Hiltbold EM, et al. 1999;194:143-149. 4. Purcell AW, et al. 2008;86(7):574-579. 5. Hanish FG, et al. 2003;33:3242-3254.

Cancer cell


HLA class I molecule

HLA complex transported via Golgi to cell surface

Peptides are combined With HLA moleculesInside the ER

Processed peptides are transportedInto the ER

Endoplasmic reticulum (ER)






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Intracellular Processing of Cancer-Associated Leads to the Presentation of a Novel Epitope Repertoire on HLA Class I Molecules on Cancer Cells

• Intracellular antigen processing of cancer-associated MUC1 by cancer cells1–3:

• Yields a novel and large T cell epitope repertoire of antignes bound to HLA class I molecules

• Allows for recognition of cancer cells by MUC1-specific cytotoxic T lymphocytes

• It is therefore reasonable to speculate that anti-tumor T Cell specific responses against the underglycosylated form of MUC1 bound to HLA class I molecules would be selectively directed at cancer cells.


PREVHOME NEXT 3. Hiltbold EM, et al. 1999;194:143-149. 4. Purcell AW, et al. 2008;86(7):574-579. 5. Hanish FG, et al. 2003;33:3242-3254.





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MUC1 Is a Scientifically Valid Target for Enhancing Immune responses Against Cancers

• MUC1 is considered a valid target for cancer immunotherapy1

• NCI objective criteria used to evaluate potentially useful cancer antigens included:1

– Therapeutic function

– Immunogenicity– Specificity

– Oncogenicity– Number of patients with antigen

positive cancers– Expression level and percent positive

cells– Stem cell expression– Number of epitopes– Cellular location of expression


PREVHOME NEXT 1. Cheever MA, et al. 2009;15(17):5323-5337.

muc1 is associated with diverse cellular functions in normal epithelial cells muc1 (mucin 1) plays a...

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cancer cells role of

glycosylated muc1 muc1

survivals of cancer

survival of cancer cells

central role

diverse cellular functions

cancer immunotherapy

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