Pathogenesis of solid tumors Leos Kren, Jana Smardova If you think we are going to discuss… •Asbestos…mesothelioma •Ultraviolet light…melanoma •HPV…cervical carcinoma •HHV8…Kaposi sarcoma •Smoking…lung, urothelial carcinomas… •Not to speak about oncogens, anti-oncogens… •You are wrong! Which of the following “hallmarks of cancer“ of the following was NOT recognized before year 2000? • •A) evading apoptosis •B) self-sufficiency in growth signals •C) tissue Invasion and metastasis •D) avoiding immune destruction •E) sustained angiogenesis • • • The hallmarks of cancer“ (Hanahan D. and Weinberg R.A. 2000, Cell 100: 57-70) • •Self-Sufficiency in Growth Signals: normal cells require mitogenic growth signals before they can move from a quiescent state into an active proliferative state. Cancer cells not. •Insensitivity to Antigrowth Signals: within a normal tissue, multiple antiproliferative signals operate to maintain cellular quiescence and tissue homeostasis •Evading Apoptosis •Limitless Replicative Potential • • • •Sustained Angiogenesis •Tissue Invasion and Metastasis • •“…a reductionist focus … has produced an extraordinary body of knowledge…new important new inroads will come from regarding tumors as complex tissues …mutant cancer cells have conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda….these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.“ • Molecular biology methods vs. histo(patho)logy in whole tissue examination •Molecular biology •Histo(patho)logy C:\Users\Leoš\Desktop\Nová složka (3)\IMG_1813.JPG C:\Users\Leoš\Desktop\Nová složka (3)\IMG_1808.JPG C:\Users\Leoš\Desktop\Nová složka (3)\IMG_1823.JPG • C:\Users\Leoš\Desktop\Nová složka (3)\IMG_1805.JPG •Hallmarks of Cancer: The Next Generation (Hanahan D. and Weinberg R.A. 2011, Cell 144: 646-674) • In oncology, therapeutic blockade of CTLA-4 and PD-1 are examples of: • •A) radiotherapy •B) chemotherapy •C) specific immunotherapy •D) non-specific immunotherapy •E) adoptive cell therapy • • Milestones of anticancer therapy •Ionizing radiation •Chemotherapy •Immunotherapy (vaccines, blockade of immune checkpoints • •Cancer Immunotherapy Named Science Magazine “Breakthrough of the Year” • 2013 Immune checkpoints (negative feedback in immune reactions – downregulate immune responses) •Normally prevents autoimmune reactions •Priming, central phase: CTLA-4 (Cytotoxic T Lymphocyte Associated Protein 4) •Effector, peripheral phase: PD-1 (Programmed Death receptor) •CTLA-4: ipilimumab… •PD-L1: nivolumab… • •Disadvantages: •So far so called financial toxicity (even in the most developed countries) •Signs of autoimmunity