Published on March 13, 2014
CANCER STEM CELLS ŁUKASZ FUŁAWKA Dolnośląskie Centrum Onkologii Zakład Patomorfologii Uniwersytet Medyczny we Wrocławiu Zakład Patomorfologii i Cytologii Onkologicznej
TUMOR HETEROGENEITY ADRENAL CORTICAL CARCINOMA
TUMOR HETEROGENEITY ANGIOSARCOMA
PROMOTION INITIATIO N PROGRESSION NORMAL CELL BENIGN TUMOR MUTATED CELL MALIGNANT TUMOR FIRST MUTATION CARCINOGENESIS PROLIFERATION MALIGNANT PHENOTYPE ACQUISITION
PROGRESSION CONCEPTS J Clin Invest. 2011;121(10):3810–3818
Cell 138, September 4, 2009 ©2009 Elsevier Inc. CSC vs. STOCHASTIC MODEL
AN OLD IDEA • 1874 – Durante - hypothesis of cancer origin from a rare population of normal cells with stem cell properties • 1875 – Cohnheim - embryonal rest theory
FIRST EXPERIMENTS • 1956 – Makino - Further evidence favoring the concept of the stem cell in ascites tumors of rats. • 1963 - Bruce & Van Der Gaag - A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. • 1967 – Pierce - Teratocarcinoma: model for a developmental concept of cancer. • 1977 - Hamburger and Salmon - hypothesis that some cancers contain a small subpopulation of cells that are similar to normal stem cells
THE NEW ERA
AACR (American Association for Cancer Research) Workshop on Cancer Stem Cells 2006
DEFINITION „cell within a tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor” AACR Workshop on Cancer Stem Cells 2006
DEFINITION CSC „can thus only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor” AACR Workshop on Cancer Stem Cells 2006
STEM CELL MARKERS Cancer Stem Cells - The Cutting Edge, Edited by Stanley Shostak, 2011
ORIGIN OF CSC - somatic stem cells - adult progenitor cells - adult somatic cells
CSC FEATURES • self-renewal • diverse progeny • immortality asymmetric mitosis
IMMORTALITY TELOMERASEACTIVITY British Journal of Cancer (2007) 96(7)
SIGNIFICANCE IN CLINICS • metastases formation • chemotherapy resistance • radiotherapy resistance • reccurence
METASTASES PRIMARY TUMOR METASTASIS
THERAPY RESISTANCE AND RECCURENCE Cancers 2011, 3(1), 319-339
PERSPECTIVES • THERAPY • DIAGNOSTICS
PROGNOSTIC MARKERS • breast cancer - a high prevalence of CSCs was associated with higher biological and molecular heterogeneity, as well as with less differentiated tumours
PROGNOSTIC MARKERS • brain tumours - the ability of tumour cells to propagate neurospheres in culture and high CD133 expression associated with a reduced time of disease-free survival and overall survival
PROGNOSTIC MARKERS • pancreatic cancer CD133+ CSCs that simultaneously displayed CXCR4 expression were directly involved in the occurrence of metastasis
CAVEATS • some tumors consists mainly of tumorigenic cells • CSC model tested on only a small subset of cancers • currently used methods underestimate the frequency of human cancer cells with tumorigenic potential • tumors contain neoplastic as well as non-neoplastic stromal and immune cells • debris from dying cells and necrotic tissue can appear indistinguishable from live cells by flow cytometry
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1. Annu Rev Cell Dev Biol. 2007;23:675-99. The biology of cancer stem cells. Lobo NA(1), Shimono Y, Qian D, Clarke MF. Author information: ...
1. Nature. 2001 Nov 1;414(6859):105-11. Stem cells, cancer, and cancer stem cells. Reya T(1), Morrison SJ, Clarke MF, Weissman IL. Author information ...