The challenge of pancreatic cancer therapy and novel treatment strategy using engineered mesenchymal stem cells

Mr, Moniri; Lj, Dai; Gl, Warnock

doi:10.1038/cgt.2013.83

Cited by 27 publications

(34 citation statements)

References 182 publications

(233 reference statements)

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“…Since, the genomic make up of each individual is different; individualized or personalized treatment is required to win the battle against cancer. In vitro engineering of mesenchymal stem cells (derived from pancreatic cancer patients) with anti-tumor genes could yield in targeting the cancer cells [88]. Due to the tumor homing capacity of the engineered mesenchymal stem cells, this strategy holds promise towards pancreatic cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

A concise review on the current understanding of pancreatic cancer stem cells

Vaz¹,

Ponnusamy²,

Seshacharyulu³

et al. 2014

J Cancer Stem Cell Res

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Several evidences suggest that a small population of cells known as cancer stem cells (CSCs) or tumor initiating stemlike cells within a tumor is capable of tumor initiation, maintenance and propagation. Recent publications have supported the existence of CSCs in pancreatic tumors. The pancreatic stem/progenitor cells, which express self-renewal markers, are identified to be present in the peribiliary gland. Based on the CSC hypothesis, mutations can lead to the transformation of stem/progenitor cells or differentiated cells into CSCs. The pancreatic CSCs express a wide array of markers such as CD44, CD24, ESA, CD133, c-MET, CXCR4, PD2/Paf1 and ALDH1. The CSCs are isolated based on surface markers or by other methods such as ALDEFLOUR assay or Hoechst 33342 dye exclusion assay. The isolated cells are further characterized by in vitro and in vivo tumorigenic assays. The most important characteristics of CSCs are its ability to self-renew and impart drug resistance towards chemotherapy. Moreover, these distinct cells display alteration of signaling pathways pertaining to CSCs such as Notch, Wnt and Shh to maintain the selfrenewal process. Failure of cancer treatment could be attributed to the therapy resistance exhibited by the CSCs. Metastasis and drug resistance in pancreatic cancer is associated with epithelial to mesenchymal transition (EMT). Furthermore, mucins, the high molecular weight proteins are found to be associated with pancreatic CSCs and EMT. Understanding the underlying molecular pathways that aid in the metastatic and drug resistant nature of these distinct cells will aid in targeting these cells. Overall, this review focuses on the various aspects of pancreatic adult/stem progenitors, CSC hypothesis, its markers, pathways, niche, EMT and novel therapeutic drugs used for the elimination of pancreatic CSCs.

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Section: Discussionmentioning

confidence: 99%

A concise review on the current understanding of pancreatic cancer stem cells

Vaz¹,

Ponnusamy²,

Seshacharyulu³

et al. 2014

J Cancer Stem Cell Res

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“…MSCs possess the ability of self-renewal, multiple differentiation potential, specific homing to tumors, and low immunogenicity (3,10,11). MSCs are being used increasingly for cancer treatment (12)(13)(14). Various reports state that MSCs can promote the progression of breast cancer and colon cancer (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Various reports state that MSCs can promote the progression of breast cancer and colon cancer (15,16). Other reports have demonstrated that MSCs can inhibit the growth of pancreatic cancer, Kaposi's sarcoma and breast cancer (13,17,18). In breast cancer, the effect of MSCs is controversial.…”

Section: Introductionmentioning

confidence: 99%

Perichondrium mesenchymal stem cells inhibit the growth of breast cancer cells via the DKK-1/Wnt/β-catenin signaling pathway

Cai

Yang

et al. 2016

Oncology Reports

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In recent years, mesenchymal stem cells (MSCs), which possess the ability to specifically home to tumor sites, with the potential of multi-directional differentiation and low immunogenicity, have been reported to inhibit the growth of various types of tumors. In the present study, we isolated MSCs from the rib perichondrium (PMSCs). By comparing PMSCs with bone marrow‑derived mesenchymal stem cells (BMSCs), we demonstrated that PMSCs present biological characteristics similar to those of BMSCs. Furthermore, we explored the effect and antitumor mechanism of PMSCs in rat SHZ-88 breast cancer cells. The growth, migration and invasion of the SHZ-88 cells were significantly inhibited, and the Wnt/β-catenin pathway and its target genes were downregulated in the SHZ-88 cells by PMSC-conditioned medium. The expression level of dickkopf-1 (DKK-1) was higher in the PMSCs than that noted in the SHZ-88 cells. Neutralization of DKK-1 in the PMSC‑conditioned medium attenuated the inhibitory effects of PMSCs on SHZ-88 cells. Therefore, PMSC-secreted DKK-1 is involved in the inhibition of SHZ-88 cell growth, migration and invasion, via the Wnt/β‑catenin signaling pathway. In addition, we demonstrated that PMSCs inhibited the growth of breast cancer in vivo and prolonged the survival time of tumor‑bearing rats. PMSCs inhibited the growth of transplanted breast tumors through the Wnt/β-catenin signaling pathway. In conclusion, our data confirmed that MSCs derived from the perichondrium present biological characteristics similar to those of BMSCs and inhibit the growth of breast cancer cells through the Wnt/β-catenin signaling pathway in vitro and in vivo. DKK-1 secreted by PMSCs played a vital role in controlling the Wnt/β-catenin signaling pathway in breast cancer.

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“…Approximately 90% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), an exocrine pancreatic tumor that resembles the cells lining the pancreatic duct (1)(2)(3). Pancreatic cancer is a highly aggressive malignancy with a notoriously dismal prognosis, and currently available therapies are only minimally effective in treating this disease (4)(5)(6). Pancreatic cancer ranks fourth in cancer mortality and accounts for <7% of all cancer-related death (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

“…Pancreatic cancer ranks fourth in cancer mortality and accounts for <7% of all cancer-related death (1)(2)(3). This poor clinical outcome may be due to the prominent resistance to drugs and radiation therapies (4)(5)(6)(7). The majority of pancreatic cancer has K-ras mutations with 90% possessing activating mutations in this oncogene (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro

Yamaguchi

Osuka

Weitzmann

et al. 2016

International Journal of Oncology

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Approximately 90% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a highly aggressive malignancy and is one of the deadliest. This poor clinical outcome is due to the prominent resistance of pancreatic cancer to drug and radiation therapies. Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various types of cells including tumor tissues. We demonstrated that the prolonged survival is induced in PDAC patients with increased regucalcin gene expression using a dataset of PDAC obtained from GEO database (GSE17891) together with the clinical annotation data file. Moreover, overexpression of regucalcin with full length was demonstrated to suppress the proliferation, cell death and migration in human pancreatic cancer MIA PaCa-2 (K-ras mutated) cells that possess resistance to drug and radiation therapies. Suppressive effects of regucalcin on cell proliferation and death were not seen in the cells overexpressed with regucalcin cDNA alternatively spliced variants (deleted exon 4 or deleted exon 4 and 5). Regucalcin was suggested to induce G1 and G2/M phase cell cycle arrest in MIA PaCa-2 cells. Suppressive effects of regucalcin on cell proliferation were independent of cell death. Overexpression of regucalcin was found to suppress signaling pathways including Akt, MAP kinase and SAPK/JNK, to increase the protein levels of p53, a tumor suppresser, and to decrease K-ras, c-fos and c-jun, a oncogene, by suppressing signaling pathways that are related to signaling of K-ras. Regucalcin may play a potential role as a suppressor protein in human pancreatic cancer.

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The challenge of pancreatic cancer therapy and novel treatment strategy using engineered mesenchymal stem cells

Cited by 27 publications

References 182 publications

A concise review on the current understanding of pancreatic cancer stem cells

A concise review on the current understanding of pancreatic cancer stem cells

Perichondrium mesenchymal stem cells inhibit the growth of breast cancer cells via the DKK-1/Wnt/β-catenin signaling pathway

Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro

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