Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

[Rich66]

1: J Immunol. 2009 Jun 1;182(11):7287-96. Links

Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.

Todaro M, D'Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G.
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vgamma9Vdelta2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-alpha and IFN-gamma) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vgamma9Vdelta2 T cells to sensitized targets. Vgamma9Vdelta2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.

Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods

• It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.

Results

• Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
• Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
• The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
• The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.