Chemoresistant Cancer Stem-like Cells Research Articles

Co-Delivery Polymeric Poly(Lactic-Co-Glycolic Acid) (PLGA) Nanoparticles to Target Cancer Stem-Like Cells.

Nanoparticle drug delivery has been promoted as an effective mode of delivering antineoplastic therapeutics. However, most nanoparticle designs fail to consider the multifaceted tumor microenvironment (TME) that produce pro-tumoral niches, which are often resistant to chemo- and targeted therapies. In order to target the chemoresistant cancer stem-like cells (CSCs) and their supportive TME, in this chapter we describe a nanoparticle-based targeted co-delivery that addresses the paracrine interactions between CSC and non-cancerous mesenchymal stem cells (MSCs) in the TME. Carcinoma-activated MSCs have been shown to increase the chemoresistance and metastasis of CSC. Yet their contributions to protect the CSC TME have not yet been systematically investigated in the design of nanoparticles for drug delivery. Therefore, we describe the fabrication of degradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (120-200nm), generated with an electrospraying process that encapsulates both a conventional chemotherapeutic, paclitaxel, and a targeted tyrosine kinase inhibitor, sunitinib, to limit MSC interactions with CSC. In the 3D hetero-spheroid model that comprises both CSCs and MSCs, the delivery of sunitinib as a free drug disrupted the MSC-protected CSC stemness and migration. Therefore, this chapter describes the co-delivery of paclitaxel and sunitinib via PLGA nanoparticles as a potential targeted therapy strategy for targeting CSCs. Overall, nanoparticles can provide an effective delivery platform for targeting CSCs and their TME together. Forthcoming studies can corroborate similar combined therapies with nanoparticles to improve the killing of CSC and chemoresistant cancer cells, thereby improving treatment efficiency.

Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma.

Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC.

Abstract 71: NEDD8-activating enzyme inhibitor MLN4924 reduces cell viability and induces apoptosis in chemoresistant cancer stem-like cells of human urothelial carcinomas in vitro and in vivo

Abstract Emerging evidence indicates that cancer stem cells (CSCs) may play a crucial role in cancer tumorigenesis, metastasis, and drug resistance. To develop treatment to inhibit CSCs provides promising target for cancer therapy. In this study, we identified a subpopulation of chemoresistant cancer stem-like cells of UCs (T24/R) after chemotherapeutic drug selection from T24, a bladder UC cell line. The T24/R cells displayed stemness markers (SOX2, Nanog, and Kruppel-like factor 4), high tumorigenicity in vivo, and enhanced invasion ability because of their epithelial-mesenchymal transition (EMT) properties. A neddylation inhibitor, MLN4924, efficiently inhibited viability and migration as well as induced apoptosis in the T24/R cells with concomitant suppression of stemness and EMT markers. Our findings suggest that MLN4924 effeiciently suppressed chemoresistant cancer stem-like UC cells and was a promising agent to conquer drug resistance in human bladder UCs. Citation Format: Shih-Ming Liao, Fu-Shun Hsu, Shao-Ping Yang, Yu-Wei Chang, Po-Ming Chow, Yeong-Shiau Pu, Yu-Chieh Tsai, Kuan-Lin Kuo, Kuo-How Huang. NEDD8-activating enzyme inhibitor MLN4924 reduces cell viability and induces apoptosis in chemoresistant cancer stem-like cells of human urothelial carcinomas in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 71.

A new strategy for enhancing antitumor immune response using dendritic cells loaded with chemo-resistant cancer stem-like cells in experimental mice model

Background and aimCancer stem cells (CSCs) are rare cell population present in the tumor bulk that are thought to be the reason for treatment failure following chemotherapy in terms of their intrinsic chemo-resistance. Our study aimed to develop an effective therapeutic strategy to target chemo-resistant cancer stem – like cells population in solid Ehrlich carcinoma (SEC) mice model using dendritic cells (DCs) loaded with enriched tumor cells lysate bearing CSC-like phenotype as a vaccine. Materials and methodsEhrlich carcinoma cell line was exposed to different concentrations of cisplatin, doxorubicin, or paclitaxel. Drug treatment that resulted in drug surviving cells with the highest expression of CSCs markers (CD44+/CD24−) was selected to obtain enriched cell cultures with resistant CSCs population. Dendritic cells were isolated from mice bone marrow, pulsed with enriched CSC lysate, analyzed and identified (CD11c, CD83 and CD86). SEC-bearing mice were treated with loaded or unloaded DCs either as single treatment or in combination with repeated low doses of cisplatin. IFN- γ serum level and p53gene expression in tumor tissues were determined by ELISA and real-time PCR, respectively. Results and conclusionThe results revealed that vaccination with CSC loaded DCs significantly reduced tumor size, prolonged survival rate, increased IFN-γ serum levels, and upregulated p53gene expression in SEC bearing mice. These findings were more evident and significant in the group co-treated with CSC-DC and cisplatin rather than other treated groups. This study opens the field for combining CSC-targeted immunotherapy with repeated low doses chemotherapy as an effective strategy to improve anticancer immune responses.

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives.

Chemotherapy for pancreatic cancer has diversified following the addition of more treatment regimens; however, in spite of this, pancreatic cancer remains a fatal disease. Preoperative (neoadjuvant) chemotherapy (NAC) or neoadjuvant chemoradiation therapy (NACRT) has been developed and implemented. For patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), a number of clinical trials have been conducted; NACRT was demonstrated to improve resectability, R0 resection rate, overall survival rate, disease-free survival rate and even an LAPC and BRPC survival advantage over NAC. However, from the knowledge obtained from resected specimens following preoperative treatment, residual pancreatic cancer tissues following NAC are rich in chemoresistant cancer stem-like cells and epithelial-mesenchymal transition (EMT) markers. Conversely, metformin, angiotensin receptor blocker, statins and low-dose paclitaxel are well-known as drugs that inhibit EMT, which is associated with cancer stem cell-like characteristics. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities in the treatment of pancreatic cancer. Furthermore, gemcitabine (GEM) affects antitumor immunity by stimulating the expression of major histocompatibility complex class I-related chain A on the surface of cancer cells to enhance the cytotoxicity of natural killer cells. Considering EMT and antitumor immunity, there is a possibility that GEM and nanoparticle albumin-bound paclitaxel therapy is the most suitable regimen for treating pancreatic cancer. However, even as preoperative treatment progresses, R0 resection is the most important factor for the long-term survival of pancreatic cancer patients.