140 Chapter 8 GENERAL DISCUSSION Tumor heterogeneity is a major challenge in the design of effective treatment strategies, as it affects tumor behavior and therapeutic resistance. Biomarkers to direct the treatment of the individual cancer patient are essential to optimize treatment efficacy and prevent unnecessary therapies and their associated side effects. Beyond biomarkers that determine ex vivo biological characteristics, molecular positron-emission-tomography (PET) imaging can characterize in vivo patient and tumor heterogeneity in a non-invasive way. In this thesis, we have shown the prospect of molecular PET imaging as a tool to steer the treatment of cancer patients based on differences in the tumor biology. Exploring tumor heterogeneity with molecular imaging Current targets for molecular imaging to explore tumor heterogeneity include metabolic pathways (e.g., glucose metabolism), targets that are abundantly and almost exclusively present on tumor cells (e.g., Carbonic anhydrase IX (CAIX)), as well as targets with a physiological expression on immune and tumor cells (Programmed cell death- Ligand-1 (PD-L1)). Familiarity with the pathophysiology of target expression and tracer behavior is essential to optimally position the available imaging tools in the oncological context. Glucose metabolism One of the key alterations observed in cancer cells, is the increased glucose consumption which is associated with a high glycolytic rate of cancer cells, the Warburg effect2. The radiotracer 18F-fluoro-2-deoxy-D-glucose ([18F]FDG) is a glucose analogue, and accumulation of [18F]FDG in tissue is proportional to the amount of glucose consumption. Since increased glucose consumption is characteristic for most cancers, [18F]FDG imaging has become an essential tool for the diagnosis, staging and therapeutic evaluation of many tumor types3. Variable [18F]FDG uptake is likely related to biological features of individual cancers, even though the reason and prognostic relevance of the biological heterogeneity is not always clear. In some tumors, higher [18F]FDG tumor uptake has been associated with more aggressive tumor biology and prognosis4. In addition, [18F]FDG PET/CT has not only proven to be valuable as a diagnostic and staging/evaluation tool, but also has prognostic value. Our data on patients with metastatic clear cell renal cell carcinoma (mccRCC) illustrates this prognostic potential in a subset of patients with an expected indolent disease (chapter 3). CAIX The expression of CAIX antigen is regulated by the transcription factor hypoxia-inducible factor 1α (HIF-1α). In normoxic conditions, HIF-1α is degraded through binding to the Von Hippel Lindau (VHL) protein. Under hypoxic conditions, the VHL-binding is inhibited which leads to an accumulation of HIF-1α that ultimately causes the transcription of hypoxia-inducible genes such as CAIX5. This upregulation of CAIX in response to hypoxia has been associated with disease progression6.
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