Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

Abstract

This study was designed to analyze the impact of multi-targeted tyrosine kinase inhibitors on the cancer stem cell subpopulation in renal cell cancer. The second objective was to evaluate the effect of tumor growth inhibition related to a tumor niche factor - oxygen deprivation - as hypoxia develops along with the anti-angiogenic activity of tyrosine kinase inhibitors in renal tumors. Cells were treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, in 2D and 3D culture conditions. Cell proliferation along with drug toxicity were evaluated. It was shown that the proliferation rate of cancer stem cells was decreased by the tyrosine kinase inhibitors. The efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions. We conclude that understanding the complex molecular interaction feedback loops between differentiated cancer cells, cancer stem cells and the tumor microenvironment in 3D culture should aid the identification of novel treatment targets and to evalute the efficacy of renal cancer therapies. Cell-cell interaction may represent a critical microenvironmental factor regulating cancer stem cell self-renewal potential, enhancing the stem cell phenotype and limiting drug toxicity. At the same time the role of hypoxia in renal cancer stem cell biology is also significant.

Alternative splice variants of DCLK1 mark cancer stem cells, promote self‐renewal and drug‐resistance, and can be targeted to inhibit tumorigenesis in kidney cancer

“…Anti‐proliferative activity is a secondary mechanism of RTKI anti‐tumor activity, and some reports suggest that this activity may be overcome through EMT induction, TSC resistance or other mechanisms . Other findings show TSCs which resist this activity can undergo endothelial differentiation in which they become susceptible, or that TSCs become susceptible at increased dose . To determine whether DCLK1 may have a role in angiogenic/vasculogenic activity that RTKIs target, we performed a surrogate assay using HUVEC endothelial cells plated in growth factor reduced matrigel with or without 200 nM of sunitinib and with or without supportive ACHN cells pretransfected with scrambled or DCLK1‐specific siRNA for 48 hr plated in 0.4 μm transwells.…”

The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)

“…The simultaneous inhibition of these targets induces a reduction in tumor vascularization and triggers cancer cell apoptosis. It has been recommended as a drug in renal cell carcinoma and in GISTs (138,139). Furthermore, since sunitinib targets many different receptors, it leads to dermatologic toxic side effects such as hand-foot syndrome (140).…”

Functional significance of CD105-positive cells in papillary renal cell carcinoma

“…1). As a positive control, HKCSCs obtained from a primary papillary RCC tumor [30] were used, but the CD105+ subpopulation was hardly detectable in this cell line. At the same time, a substantial number of CD105+ cells were detected in an ASE cell line, which were normal renal cells of embryonic origin (Fig.…”