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GROUP 6

Leandro Weber Souza

Cancer differentiation is an effectivetherapy

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Hallmarks of Cancer (Pathology)

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Additional Hallmarks of Cancer

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Pathology(Hallmarks)

Etiopathogenesis(Model)

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Stem Cell Model of Cancer

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For Against

Role ofmicro-

environment

Not alltumours

contain CSCs

Diff.sensitises

CSC

Diff. cells arenot

tumorigenic

Cancer differentiation is an effectiveTx

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BMP4 induces differentiation of CSC andincreases response to chemotherapy

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BMP4 induces differentiation of CSC andincreases response to chemotherapy

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BMP4 induces differentiation of CSC andincreases response to chemotherapy

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Anti-DLL4 reduces CSC frequency

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Anti-DLL4 reduces CSC frequency

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For Against

Role ofmicro-

environment

Not alltumours

contain CSCs

Diff.sensitises

CSC

Diff. cells arenot

tumorigenic

Cancer differentiation is an effectiveTx

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CSCs have been proven in many cancers

However, not all cancers contain stem cells

i.e. do not display significant heterogeneity

It is questionable whether (active) differentiationattempts will aid Tx in these cases

Not all cancers contain CSCs

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CSCs are regulated by themicroenvironment

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CSCs are regulated by themicroenvironment

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CSCs are regulated by themicroenvironment

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CSCs are regulated by themicroenvironment

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Epithelial-Mesenchymal Transition

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Epithelial-Mesenchymal Transition

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Epithelial-Mesenchymal Transition

Tumor growth leads to resistance

to oxygen deprivation, complete

loss of epithelial features and

development of mesenchymal

and motile phenotypeNormal cell

Transformed cell

Invasive cell

Metastatic cell

z

From Sheila Krishnadath, MD,PhD 

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Conclusion

Pre-treatment

Dynamical CSC model  – CSC specific

therapy

A

B

Post-treatment Relapse

C

Hierarchical CSC model  – CSC specifictherapy

Hierarchical CSC model  – conventionaltherapy

- Target CSC

- Target microenvironment

- and their interactions From Felipe de Souza e Melo

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Hanahan, Douglas, and Robert A. Weinberg. “The Hallmarks of Cancer.” Cell 100, no. 1 (January 7,2000): 57-70.

Hanahan, Douglas, and Robert A. Weinberg. “Hallmarks of Cancer: The Next Generation.” Cell 144,no. 5 (March 4, 2011): 646-674.

Hoey, Timothy, Wan-Ching Yen, Fumiko Axelrod, Jesspreet Basi, Lucas Donigian, Scott Dylla,Maureen Fitch-Bruhns, et al. “DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-InitiatingCell Frequency.” Cell Stem Cell 5, no. 2 (August 7, 2009): 168-177.

Kelly, Priscilla N., Aleksandar Dakic, Jerry M. Adams, Stephen L. Nutt, and Andreas Strasser. “TumorGrowth Need Not Be Driven by Rare Cancer Stem Cells.” Science 317, no. 5836 (July 20, 2007): 337.

Lombardo, Ylenia, Alessandro Scopelliti, Patrizia Cammareri, Matilde Todaro, Flora Iovino, LuciaRicci-Vitiani, Gaspare Gulotta, Francesco Dieli, Ruggero de Maria, and Giorgio Stassi. “BoneMorphogenetic Protein 4 Induces Differentiation of Colorectal Cancer Stem Cells and Increases

Their Response to Chemotherapy in Mice.” Gastroenterology 140, no. 1 (January 2011): 297-309.e6. Mani, Sendurai A., Wenjun Guo, Mai-Jing Liao, Elinor Ng. Eaton, Ayyakkannu Ayyanan, Alicia Y. Zhou,

Mary Brooks, et al. “The Epithelial-Mesenchymal Transition Generates Cells with Properties of StemCells.” Cell 133, no. 4 (May 16, 2008): 704-715.

Vermeulen, Louis, Felipe De Sousa E Melo, Maartje van der Heijden, Kate Cameron, Joan H. de Jong,Tijana Borovski, Jurriaan B. Tuynman, et al. “Wnt activity defines colon cancer stem cells and isregulated by the microenvironment.” Nat Cell Biol 12, no. 5 (May 2010): 468-476.