Biological responses to tumor hypoxia & their potential as therapeutic targets
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Lecture by Dr. Brad Wouters in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III". For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia
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Biological responses to tumor hypoxia & their potential as therapeutic targets
- 1. Biological responses to tumor hypoxia and their potential as therapeutic targets Brad Wouters This course is funded with the support of the METOXIA project under the FP7 Programme.
- 2. Learning Objectives Understand the importance of hypoxia to phenotypic diversity in tumours Identify mechanisms that promote hypoxia tolerance in tumours Understand why mTOR regulation by hypoxia is important Understand why UPR signaling during hypoxia is important This course is funded with the support of the METOXIA project under the FP7 Programme.
- 3. Phenotypic diversity exists within tumors Genetic, epigenetic, microenvironmental Cellular ‘individuality’ Therapy ‘escape’ Therapies are not equally effective against all tumor cells
- 4. Tumor hypoxia influences cancer biology Gene expression Cell phenotype • Cell signaling • Proliferation • Metabolism • Metastasis • Angiogenesis • DNA Repair, • Stem cells • Treatment resistance
- 5. Heterogeneity in Oxygenation Amount Severity Distribution Photos courtesy of Bert van der Kogel Time
- 6. The microenvironment is patient specific Cancer genetics influence the microenvironment
- 7. • Metabolism Genes • Angiogenesis • Genetic Instability Phenotype • Growth/proliferation • Metastasis • Stemness? Environment
- 8. Hypoxia is a stable phenotype of pancreatic cancers associated with aggressive disease Chang and Hedley, 2011,Cancer Research
- 9. Hypoxia varies widely amongst patients Hypoxic fraction in head and neck cancer Hypoxic fraction ranges from 0-100%
- 10. Hypoxia predicts for poor outcome 397 head and neck patients – 7 centers Nordsmark M et al, Radiother Oncol. 2005
- 11. Hypoxia and Treatment Outcome Cervix cancer – hypoxia predicts for overall survival Disease-free survival Metastasis Hypoxic Hypoxic
- 12. PSA Failure-Free Rate by Tumor Hypoxia All Patients (n=247) Bulk Patients (n=144) 1.0 Biochemical failure free rate 0.9 0.8 p=0.03 p=0.009 0.7 Oxic (HP10=20%) Oxic (HP10=20%) Hypoxic (HP10=80%) Hypoxic (HP10=80%) 0.6 0 20 40 60 0 20 40 60 Time (month) Time (month) Milosevic et al, in press
- 13. What determines tumour hypoxia?
- 14. 1) Selection for hypoxia tolerant cells Graeber TG et al. Nature 379(6560): 88-91, 1996
- 15. Hypoxia and Selection – The case of p53 Hypoxia
- 16. Hypoxia-mediated mutation selection Graeber TG et al. Nature 379(6560): 88-91, 1996
- 17. 2) Hypoxia Initiates Adaptive Responses Wouters and Koritzinsky, Nature Reviews Cancer 2008
- 18. mTOR is a central metabolic regulator that responds to environmental signals Hypoxia Metabolism Protein synthesis Cell growth/proliferation
- 19. mTOR inhibition in hypoxic tumor areas Hedley et al, unpublished
- 20. Hypoxia suppresses mTOR and metabolism PTEN Metabolism Growth Proliferation Survival Koritzinsky et al, EMBO, 2006
- 21. mTOR inhibition promotes hypoxia tolerance in vivo Measure hypoxia Measure hypoxia Inject cells +/- Dox 4E 4E OE Rouschop et al, 2011
- 22. mTOR inhibition during hypoxia promotes therapy resistance IR response Inject cells +/- Dox 4E 4E OE 4 4 3 3 Relative tumour size Relative tumour size 15Gy 15Gy 2 2 1 PCDNA5 1 eIF4E Dox Dox 0 0 -7 0 7 14 21 28 35 42 49 56 63 70 -7 0 7 14 21 28 35 42 49 56 63 70 Days Days Rouschop et al, 2011
- 23. Hypoxia activates all 3 arms of the UPR Anoxia [hrs] 0 1 2 4 8 eIF2α-P Anoxia eIF2α [hrs] 0 1 2 4 6 * ATF-6 Anoxia [hrs] 0 .5 2 6 XBP-1u XBP-1s Wouters and Koritzinsky, Nature Reviews Cancer 2008
- 24. Targeting the UPR sensitizes cells to hypoxia Inject cells +/- Dox DN OE
- 25. Targeting the UPR improves treatment IR Inject cells +/- Dox 4 DN 3 15Gy Relative tumor size 2 1 0 Dox -7 0 7 14 21 28 35 42 49 56 63 70 Days
- 26. Why is UPR signaling important ? Phenotype Tolerance Metastasis Autophagy LAMP3 LC3B, ATG5 pH control ROS, redox CA9 Glutathione biosynthesis Amino acid biosynthesis
- 27. Hypoxia inhibits translation through PERK HeLa C 1 2 4 8 C DTT eIF2 - P actin Koumenis et al., MCB, 2002
- 28. Hypoxia inhibits mRNA translation transcription translation DNA RNA Protein Hypoxia Hypoxia Hypoxia
- 29. Hypoxia inhibits overall protein synthesis Hypoxia Preserve energy Change which genes (ATP) are made into proteins
- 30. PERK/UPR signaling protects against ROS induced by fluctuating hypoxia
- 31. The UPR regulates CA9 van den Beucken and Wouters, unpublished data
- 32. The UPR Enables Autophagy 1 – Provide energy and nutrients during starvation 2 – Remove damaged organelles and protein aggregates Both processes are cytoprotective
- 33. Autophagy is activated in hypoxic tumors N SCCNij172 Lc3b/pimo/vessels
- 34. The UPR induces LC3B via ATF4
- 35. LC3 is turned over during autophagy Geng and Klionsky, EMBO reports, 2008
- 36. LC3B protein is lost in UPR deficient cells HCT116 U373 Wildtype Wildtype LC3B protein LC3B protein PERK defective PERK defective
- 37. Hypoxia and the UPR stimulate autophagy Energy Removal of toxins Rouschop, JCI, 2011
- 38. PERK regulates energy metabolism
- 39. Inhibition of protein synthesis Bioenergetic homeostasis and protection against ROS Metabolism
- 40. Summary • Hypoxia causes phenotypic diversity in tumours • Hypoxia in patients is variable and determined by mechanisms that influence hypoxia tolerance • Hypoxia tolerance is influenced by mTOR and UPR regulation • UPR influences hypoxia tolerance through multiple mechanisms – ROS, pH, autophagy, metabolism
Hinweis der Redaktion
- A key challenge for treating cancer effectively arises from phenotypic diversity within individual cancers. This is especially true when we are considering potentially curative therapies.
- The genetic and epigenetic changes in tumor cells can tell us a lot about the nature of tumors, but is not enough to fully understand them. This is because the tumor microenvironment plays a critical role on the behavior of tumors by regulating many phenotypes that we associate with cancer.
- Understanding the role and function of the genes and pathways altered in cancer requires us to consider them in context. There is evidence to suggest that genes/pathways are altered in cancer not only to facilitate cell autonomous functions (proliferation/survival) but also to influence their microenvironment. Simialrly, the genes that do provide cell autonmous advantages can have dramatic consequences for the micorenvironment. Eg apopotosis. Consequently the phenotype of both normal tissues, and tumors is a complex interaction between genes and their environment.
- Importance goes beyond therapy resistance
- Several key pathways have been recognized as important determinants of hypoxia tolerance, and thus the proportion of viable hypoxic cells in human tumors. These pathways are distinct, show unique dependencies on oxygen concentration, and influence many different downstream signalling pathways. However, a common theme that emerges from our current understanding is the ability of these pathways to transiently reprogram metabolism in a way that promotes energy homeostasis and cell survival.
- Ubiquitin like molecule that is turned over
- We are addressing this question – what is the importance of mTOR/4F regulation. We hypothesize that tumor cells maintain control over mTOR mediated translation to faciliate survival