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
Biological responses to tumor hypoxia & their potential as therapeutic targets
Biological responses to tumorhypoxia and their potential as therapeutic targets Brad Wouters This course is funded with the support of the METOXIA project under the FP7 Programme.
Learning ObjectivesUnderstand the importance of hypoxia to phenotypicdiversity in tumoursIdentify mechanisms that promote hypoxia tolerance intumoursUnderstand why mTOR regulation by hypoxia isimportantUnderstand why UPR signaling during hypoxia isimportant This course is funded with the support of the METOXIA project under the FP7 Programme.
Phenotypic diversity exists within tumorsGenetic, epigenetic,microenvironmentalCellular ‘individuality’Therapy ‘escape’Therapies are notequally effectiveagainst all tumorcells
Tumor hypoxia influences cancer biologyGene expressionCell phenotype• Cell signaling• Proliferation• Metabolism• Metastasis• Angiogenesis• DNA Repair,• Stem cells• Treatment resistance
Heterogeneity in OxygenationAmount SeverityDistribution Photos courtesy of Bert van der Kogel Time
The microenvironment is patient specific Cancer genetics influence the microenvironment
Inhibition of proteinsynthesis Bioenergetic homeostasis and protection against ROS Metabolism
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