Download מדינת ישראל state of israel משרד הבריאות ministry of health לשכת המדען

‫מדינת ישראל‬
STATE OF ISRAEL
MINISTRY OF HEALTH
CHIEF SCIENTIST OFFICE
JERUSALEM
‫משרד הבריאות‬
‫לשכת המדען הראשי‬
‫ירושלים‬
Research Number: 300000-6039
Title: The role of cancer stem cells in angiogenesis following cytotoxic drug therapy.
Principal Investigator: Yuval Shaked
Institute: Technion
Other Author(s):
Institute(s):
Year (Start): 2010
Year (End): 2012
Background: Tumor initiating cells (TICs) which probably display the only cells in the tumor
with a proliferative capacity, have been shown to induce angiogenesis. We hypothesized that
tumors enriched with TICs following chemotherapy, can induce angiogenesis, and may
promote tumor re-growth.
Research Hypothesis: TIC may contribute to angiogenesis and vasculogenesis.
Aims: Study the angiogenic and vaculogenic profile of TICs of various tumor types, and
assess the effects of antiangiogenic drugs on the TIC population.
Methods: To test this, we generated cultures of human cell-lines of glioma (U87), colon
(HT29), and pancreatic (PANC1) cancers either as monolayers (‘TIC-low’) or as tumorspheres (‘TIC-high’). The efficacy of antiangiogenic drug was evaluated on tumor bearing
mice, and levels of TICs was tested in treated tumors.
Results: We demonstrate that TIC-high consists of stem-cell properties by means of stem-cell
surface markers, aldehyde-dehydrogenase activity, P21 expression, and resistance to standard
therapy. TIC-high conditioned media (CM) of U87 and HT29 but not of PANC1 significantly
induced angiogenesis in vitro and in Matrigel plugs containing CM, as opposed to TIC-low
CM. Interestingly, the addition of an antiangiogenic drug to TIC-high CM of U87 and HT29,
but not TIC-high nor TIC-low CM of PANC1 inhibited microvessel sprouting. Mouse studies
investigating the angiogenesis properties of TICs from U87 and PANC1 following
chemotherapy and antiangiogenic therapy revealed that antiangiogenic drug therapy is
effective in U87 but not PANC1. In addition, TICs from a variety of glioblastoma cells
revealed a significant change in the angiogenesis profile, and as a result, diverse affect of
antiangiogenic drugs was observed in such conditions.
Discussion and conclusions: Our results may suggest that both glioma and colon carcinoma,
but not pancreatic adenocarcinoma, can induce angiogenesis following chemotherapy, which
may explain why antiangiogenic drugs show additional treatment benefits in such cancers.
Our results also suggest that TICs enriched from different tumors can predict clinical outcome
of antiangiogenic drug based on their angiogenesis profile.
Keywords: antiangiogenic drugs, tumor initiating cells, bone marrow derived cells, cancer
stem cells.
The State of Israel
Ministry of Health
Chief Scientist Office
Israeli Medical Abstracts Repository (IMAR) J
Publications associated with the project:
1. Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA
copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances.
Segal E, Pan H, Benayoun L, Kopečková P, Shaked Y, Kopeček J, Satchi-Fainaro R.
Biomaterials. 2011 Jul;32(19):4450-63.
2. Host response to short-term, single-agent chemotherapy induces matrix
metalloproteinase-9 expression and accelerates metastasis in mice. Gingis-Velitski S,
Loven D, Benayoun L, Munster M, Bril R, Voloshin T, Alishekevitz D, Bertolini F,
Shaked Y. Cancer Res. 2011 Nov 15;71(22):6986-96.
3. G-CSF supplementation with chemotherapy can promote revascularization and
subsequent tumor regrowth: prevention by a CXCR4 antagonist. Voloshin T, GingisVelitski S, Bril R, Benayoun L, Munster M, Milsom C, Man S, Kerbel RS, Shaked Y.
Blood. 2011 Sep 22;118(12):3426-35.
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