Abstract
This study investigated molecular signals essential to sustain cancer stem cells (CSCs) and assessed their activity in the presence of secreted frizzled-related protein 4 (sFRP4) alone or in combination with chemotherapeutic drugs. SFRP4 is a known Wnt antagonist, and is also pro-apoptotic and anti-angiogenic. Additionally, sFRP4 has been demonstrated to confer chemo-sensitization and improve chemotherapeutic efficacy. CSCs were isolated from breast, prostate, and ovary tumor cell lines, and characterized using tumor-specific markers such as CD44+/CD24−/CD133+. The post-transcription data from CSCs that have undergone combinatorial treatment with sFRP4 and chemotherapeutic drugs suggest downregulation of stemness genes and upregulation of pro-apoptotic markers. The post-translational modification of CSCs demonstrated a chemo-sensitization effect of sFRP4 when used in combination with tumor-specific drugs. SFRP4 in combination with doxorubicin/cisplatin reduced the proliferative capacity of the CSC population in vitro. Wnt/β-catenin signaling is important for proliferation and self-renewal of CSCs in association with human tumorigenesis. The silencing of this signaling pathway by the application of sFRP4 suggests potential for improved in vivo chemo-responses.
Highlights
Chemotherapy, along with radiotherapy and hormone therapy, is the most common treatment for cancer
The combinatorial treatment showed significant reduction in the cancer stem cells (CSCs) marker population in all cell line-derived CSCs; in A2780 prostate CSCs, cisplatin treatment showed phenotype switching to CD44+ positive cells and only reduced the CD133+ population; this switching did not affect the inhibitory effect of combinatorial treatment
The CSCs derived from breast, prostate, and ovary tumor cell lines were treated with secreted frizzled-related protein 4 (sFRP4) (250 pg) and doxorubicin (5 μM)/cisplatin (30 μM) alone or in combination
Summary
Chemotherapy, along with radiotherapy and hormone therapy, is the most common treatment for cancer. A critical role of a small subset of tumor cells, known as cancer stem cells (CSCs), was established in tumor relapse and propagation[2, 3]. Most solid tumors, including breast, brain, prostate, ovary, mesothelioma, and colon cancer contain this small subset of self-renewing, tumor initiating cells[4]. Ovary, and prostate cancers, several CSC populations have been identified using cell surface markers (CD44+/CD133+/CD24−/low); these CSCs have shown a high clonal, invasive, and metastatic capacity, leading to resistance to radio-therapy, chemotherapeutic drugs (doxorubicin and cisplatin), and other target-specific therapy[10,11,12]. SFRP4 is one of the prominent isoforms with the capacity to chemo-sensitize tumor cells to chemotherapeutics[18, 19]. Chemo-sensitization of CSCs by sFRP4 has the potential to decrease the required chemotherapeutic load to facilitate tumor resolution
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