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…
• You are wrong!
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
• “…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
• Sustained Angiogenesis
• Tissue Invasion and Metastasis
Hallmarks of Cancer: The
Next Generation
(Hanahan D. and Weinberg
R.A. 2011, Cell 144: 646-
674)
Milestones of anticancer
therapy
• Ionizing radiation
• Chemotherapy
• Immunotherapy (vaccines, blockade of
immune checkpoints
Immune checkpoints (negative
feedback in immune reactions)
• Priming, central phase: CTLA-4 (Cytotoxic
T Lymphocyte Associated Protein 4)
• Effector, peripheral phase: PD-1
(Programmed Death receptor)
S. Pernot, World J Gastroenterol 2014
•CTLA-4: ipilimumab…
•PD-L1: nivolumab…
• Cave: so far financial toxicity (even in the
most developed countries)