Abstract
Evidences indicate that tumor development and progression towards a malignant phenotype depend not only on cancer cells themselves, but are also deeply influenced by tumor stroma reactivity. The present study uses mesenchymal stem cells from normal human uterine cervix (hUCESCs), isolated by the minimally invasive method of routine Pap cervical smear, to study their effect on the three main cell types in a tumor: cancer cells, fibroblasts and macrophages. Administration of hUCESCs-conditioned medium (CM) to a highly invasive breast cancer MDA-MB-231 cell line and to human breast tumors with high cell proliferation rates had the effect of reducing cell proliferation, modifying the cell cycle, inducing apoptosis, and decreasing invasion. In a xenograft mouse tumor model, hUCESCs-CM reduced tumor growth and increased overall survival. In cancer-associated fibroblasts, administration of hUCESCs-CM resulted in reduced cell proliferation, greater apoptosis and decreased invasion. In addition, hUCESCs-CM inhibited and reverted macrophage differentiation. The analysis of hUCESCs-CM (fresh and lyophilized) suggests that a complex paracrine signaling network could be implicated in the anti-tumor potential of hUCESCs. In light of their anti-tumor potential, the easy cell isolation method, and the fact that lyophilization of their CM conserves original properties make hUCESCs good candidates for experimental or clinical applications in anticancer therapy.
Highlights
Breast cancer is the most common malignancy in women
We show that hUCESCs and their secretome, called conditioned medium, inhibit the aggressive behavior of cancer cells in vitro and reduce tumor growth in vivo in a mouse xenograft tumor model
Isolation and characterization of hUCESCs hUCESCs obtained from exfoliation PAP smears of the uterine cervix were examined for immunophenotype using immunocytochemistry and flow cytometry, as reported previously by Eiro et al, (World Congress on Cell Science & Stem Cell Research. 2014). hUCESCs are positive for vimentin and β-catenin, and occasional cells immunostained with pan-cytokeratin antibody (Figure 1A)
Summary
Breast cancer is the most common malignancy in women. Tumor initiation is typically conceptualized as the accumulation of genetic and epigenetic mutations in the epithelium that result in recruitment of reactive stroma. Evidence exists indicating that tumor development and progression towards a malignant phenotype depend on cancer cells themselves, and on tumor stroma reactivity [1], which may often dictate tumor outcome in breast cancer [25]. The two well-studied cellular components of tumor stroma are cancer associated fibroblasts (CAFs) [6] and cancer-associated macrophages (CAMs) [7]. It has been widely reported that both are key orchestrators of tumor microenvironment, directly affecting neoplastic cell growth, neoangiogenesis, and extracellular remodelling www.impactjournals.com/oncotarget [8]. New therapeutic strategies for breast cancer should consider their effect on cancerous cells and on stromal cells
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