CANCER STEM CELLS

ŁUKASZ FUŁAWKA

Dolnośląskie Centrum Onkologii Zakład Patomorfologii

Uniwersytet Medyczny we WrocławiuZakład Patomorfologii i Cytologii Onkologicznej

TUMOR HETEROGENEITY

ADRENAL CORTICAL CARCINOMA

TUMOR HETEROGENEITY

ANGIOSARCOMA

PROMOTION

INITIATION

PROGRESSION

NORMALCELL

BENIGNTUMOR

MUTATED CELL

MALIGNANT TUMOR

FIRSTMUTATION

CARCINOGENESIS

PROLIFERATION

MALIGNANTPHENOTYPE

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

DETECTING METHOD

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

ASYMMETRIC MITOSIS

IMMORTALITYTE

LOM

ERAS

E AC

TIVI

TY

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

TARGETED THERAPY

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