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Tumor stem cells in primary human breast cancer; isolation and characterization of the pseudohypoxic phenotype

Principal investigator; Jögi, Annika, Associate Professor, PhD

Clinical speciality:

Phone: ++4640332829

Co-workers: Sven Påhlman

Research area/areas: Cancer and Oncology, Cell and Molecular Biology, Medical Biotechnology (focus on Cell Biology (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Cancer recurrence and metastasis is attributed to the presence of tumor stem cells. We hypothesize that hypoxia inducible factor-2a (HIF-2a) is one marker for breast cancer stem cells based on the recent finding in our laboratory that presence of HIF-2a positive cells in breast cancer correlates to poor prognosis and metastasis (Helczynska K, et al Cancer Res 2008). A similar correlation was found in neuroblastoma, and in this tumor HIF-2a positive cells with stem cell traits were identified. Recent data show that neuroblastoma tumor initiating cells, isolated from patient bone marrow metastases, have a phenotype similar to that found in tumors and that HIF-2a keeps their stemness by preventing differentiation (Pietras A, et al PNAS 2009). Given the similar associations between high HIF-2a protein levels, poor outcome and metastasis in both breast cancer and neuroblastoma patients, we plan in this project to 1) find conditions to grow breast cancer stem cells in vitro and as xenografts in breast fat pads of immunodeficient mice, 2) phenotypically characterize breast cancer stem cells from different sub-groups of breast cancer and 3) specifically investigate the relation between the hypoxic phenotype and stemness in the breast tumor stem cells grown as mammospheres or xenografts and test involvement of HIF-2a in breast cancer stemness. Preliminary results show heterogenous expression of stem cell markers in mammosphere cultures of primary breast tumor cells and the hypoxic response in the mammospheres is now investigated.

This project begins at the focal point, where research on the hypoxic response, and adaptation of tumor cells to the tumor microenvironment, and tumor stem cell research intersect. Today, hypoxia driven signaling is recognized as a major contributor to tumor progression and treatment failure, but its exact role(s) in cancer remains to be defined. Increased knowledge of HIF-2a positive tumor cells, and very likely among them tumor stem cells, may be of great importance since the behavior of this subpopulation has bearing on the entire tumor, e.g. induction of angiogenesis and stromal growth.

5 recent original publications

Jögi A, Brennan DJ, Rydén L, Magnusson K, Fernö M, Stål O, Borgquist S, Uhlen M, Landberg G, Påhlman S, Pontén F, Jirström K.
Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer.
Mod Pathol. 2009; 22(12): 1564-74

Jögi A, Vallon-Christersson J, Holmquist L, Axelson H, Borg A, Påhlman S.
Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior.
Exp Cell Res. 2004; 295(2): 469-87

Helczynska K, Kronblad A, Jögi A, Nilsson E, Beckman S, Landberg G, Påhlman S.
Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.
Cancer Res. 2003; 63(7): 1441-4

Jögi A, Øra I, Nilsson H, Poellinger L, Axelson H, Påhlman S.
Hypoxia-induced dedifferentiation in neuroblastoma cells.
Cancer Letters. 2003; 197(1-2): 145-50

Jögi A, Øra I, Nilsson H, Lindeheim A, Makino Y, Poellinger L, Axelson H, Påhlman S.
Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
Proc Natl Acad Sci U S A. 2002; 99(10): 7021-6.

Further publications here (new window)

Financing/year