Eta polycaprolactone (ε-PCL) implants appear to cause a partial differentiation of breast cancer lung metastasis in a murine model.

BACKGROUND: Cells in every epithelium can be roughly divided in three compartments: stem cell (SC) compartment, transient amplifying cell (TA) compartment and terminally differentiated (TD) compartment. Maturation of stem cells is characterized by epithelial stromal interaction and sequential maturational movement of stem cell's progeny through those compartments. In this work we hypothesize that providing an artificial stroma, which murine breast cancer metastatic cells can infiltrate, will induce their differentiation. METHODS: BALB/c female mice were injected with 106 isogenic 4T1 breast cancer cells labeled with GFP. After 20 days primary tumors were removed, and artificial ε-PCL implants were implanted on the contralateral side. After 10 more days mice were sacrificed and implants along with lung tissue were harvested. Mice were divided in four groups: tumor removal with sham implantation surgery (n = 5), tumor removal with ε-PCL implant (n = 5), tumor removal with VEGF enriched ε-PCL implant (n = 7) and mice without tumor with VEGF enriched ε-PCL implant (n = 3). Differentiational status of GFP + cells was assessed by Ki67 and activated caspase 3 expression, thus dividing the population in SC like cells (Ki67+/dim aCasp3-), TA like cells (Ki67+/dim aCasp3+/dim) and TD like cells (Ki67- aCasp3+/dim) on flow cytometry. RESULTS: Lung metastatic load was reduced by 33% in mice with simple ε-PCL implant when compared to tumor bearing group with no implant. Mice with VEGF enriched implants had 108% increase in lung metastatic load in comparison to tumor bearing mice with no implants. Likewise, amount of GFP + cells was higher in simple ε-PCL implant in comparison to VEGF enriched implants. Differentiation-wise, process of metastasizing to lungs reduces the average fraction of SC like cells when compared to primary tumor. This effect is made more uniform by both kinds of ε-PCL implants. The opposite process is mirrored in TA like cells compartment when it comes to averages. Effects of both types of implants on TD like cells were negligible. Furthermore, if gene expression signatures that mimic tissue compartments are analyzed in human breast cancer metastases, it turns out that TA signature is associated with increased survival probability. CONCLUSION: ε-PCL implants without VEGF can reduce metastatic loads in lungs, after primary tumor removal. Both types of implants cause lung metastasis differentiation by shifting cancer cells from SC to TA compartment, leaving the TD compartment unaffected.

Novel Thieno [2,3-b]pyridine Anticancer Compound Lowers Cancer Stem Cell Fraction Inducing Shift of Lipid to Glucose Metabolism.

Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC-MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.