Identification of Pancreatic Cancer Stem Cells and Selective Toxicity of Chemotherapeutic Agents

Adikrisna, Rama; Tanaka, Shinji; Muramatsu, Shunsuke; Aihara, Arihiro; Ban, Daisuke; Ochiai, Takanori; Irie, Tetsumi; Kudo, Atsushi; Nakamura, Noriaki; Shoji, Yasuhiro; Arii, Shigeki

doi:10.1053/j.gastro.2012.03.054

Cited by 113 publications

(99 citation statements)

References 53 publications

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“…In concordance with a CSC phenotype, these cells were characterized by expression of stem cell markers, absence of differentiation markers, high sphereforming capacity in vitro and high tumorigenicity in vivo (46). Later, similar findings have been reported for other cancers, including pancreas, prostate, head and neck, cervical and lung cancer (68)(69)(70)(71)(72). Interestingly, specific targeting of these low proteasome activity cells (LPACs) resulted in tumor regression (46,73).…”

Section: Proteasome Activity As a Csc Markersupporting

confidence: 60%

“…Interestingly, specific targeting of these low proteasome activity cells (LPACs) resulted in tumor regression (46,73). On the other hand, LPACs were more resistant to various types of treatment, such as radiotherapy (46) or chemotherapy (68)(69)(70). In a subsequent study, the group of Pajonk found that proteasome levels were downregulated in cells overexpressing Musashi-1, via inhibition of NF-YA, the most important transcription factor for the proteasomal subunits (74).…”

Section: Proteasome Activity As a Csc Markermentioning

confidence: 99%

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Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Lenos¹,

Vermeulen²

2016

Ann. Transl. Med.

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A population of stem-like cells in tumors, the so-called cancer stem cells (CSCs), are being held responsible for therapy resistance and tumor recurrence. In analogy with normal stem cells, CSCs possess the capacity of long term self-renewal and multilineage differentiation. CSCs are believed to be more resistant to various therapies compared to their differentiated offspring and therefore the cause of tumor relapse. Markers for CSCs have been identified using xenograft transplantation assays and lineage tracing in mouse models, however the specificity and validity of many of these markers is under debate. Recently, low proteasome activity has been postulated as a novel CSC marker. In several solid malignancies a small subset of low proteasomal activity cells with CSC characteristics were identified, suggesting that proteasomal activity might be a functional marker for CSCs. In this perspective, we will discuss a recent study by Munakata et al., describing a population of colorectal cancer cells with CSC properties, characterized by low proteasome activity and treatment resistance. We will put this finding in a broader view by discussing the challenges and issues inherent with CSC identification, as well as some emerging insights in the CSC concept.

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Section: Proteasome Activity As a Csc Markersupporting

confidence: 60%

Section: Proteasome Activity As a Csc Markermentioning

confidence: 99%

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Lenos¹,

Vermeulen²

2016

Ann. Transl. Med.

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“…we observed that the fractions of ZsGreen + cells were 1.7 and 5.1% in the U2-OS and MG-63 cells, respectively. Previous reports have shown that the fractions of ZsGreen + cells were <4% in u87MG (13) and 0.5% in Panc-1 (14). The proteasome activity of ZsGreen + cells are lower than ZsGreen -cells in MG-63, whereas no difference was found in U2-OS; this is likely because this proteasome activity assay can detect partial proteasome activity.…”

Section: Discussionmentioning

confidence: 68%

“…The ubiquitinproteasome system is the major non-lysosomal system for the degradation of intracellular proteins. Recently, cancer cells with low proteasome activity have been identified as TICs in patients with breast cancer, glioma (13), pancreatic cancer (14), and esophageal cancer (15) using a fluorescence marker system for the level of proteasome activity. However, no study has reported the identification of TICs in human osteosarcoma cell lines on the basis of low proteasome activity.…”

Section: Introductionmentioning

confidence: 99%

Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity

Tamari

Hayashi

Ishii

et al. 2014

International Journal of Oncology

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Abstract. Osteosarcoma is the most common primary bone malignancy in pediatric and adolescent populations. Recurrence and metastatic potential can be due to a subpopulation of cells with stem cell-like characteristics, such as tumor-initiating cells (TICs), which maintain the capacity to regenerate entire tumors. Targeting the TICs in osteosarcoma is a promising avenue for the development of new therapies for this devastating disease. TICs are usually quiescent with a low protein turnover, decreased metabolism, and downregulation of proteasome activity. Recently, cancer cells with low proteasome activity have been identified as TICs in several types of cancer. We stably infected two osteosarcoma cell lines, MG-63 and U2-OS, with an expression vector for a fusion protein between the green fluorescent protein, ZsGreen, and the C-terminal degron of the murine ornithine decarboxylase to monitor the 26S proteasome activity in living cells. We separated the osteosarcoma cells with low proteasome activity using fluorescence-activated cell sorting (FACS) and verified whether these ZsGreen + cells had TIC-like properties. The ZsGreen + cells showed enhanced sphere formation capacity and underwent asymmetric divisions into ZsGreen + and ZsGreen -cells, whereas ZsGreen -cells underwent only symmetric divisions into ZsGreen -cells. Moreover, the ZsGreen + cells were more chemo-and radioresistant. Thus, the present study demonstrated that chemoradiation-resistant TICs can be visualized by this system and suggested the rationale for further study of osteosarcoma stem cells. IntroductionOsteosarcoma is the most common primary bone malignancy in children and young adults. Osteosarcoma occurs in the long bones of the limbs, particularly in the distal femur and proximal tibia. Osteosarcoma is a locally aggressive tumor and tends to produce early distant metastases, particularly to the lung. Before 1970, amputation was the only treatment for osteosarcoma patients and 80% patients died of metastatic disease (1). Since the 1970s, the combination of limb-sparing surgery and conventional chemotherapy agents, including methotrexate (MTX), cisplatin (CDDP), and doxorubicin, has been used to treat osteosarcoma. However, the 5-year patient survival has plateaued at ~60-70% (2).Tumors are organized into a hierarchy of heterogeneous cell populations. Recurrence and metastatic potential may be due to a subpopulation of cells with stem cell-like characteristics, such as cancer stem cells (CSCs) or tumor-initiating cells (TICs), which maintain the capacity to regenerate entire tumors (3). Targeting the TICs in osteosarcoma may be a promising avenue to explore for the development of new therapies for this devastating disease.Increasing evidence of the existence of TICs in patients with osteosarcoma has been reported. Identification of osteosarcoma TICs has been performed using CD133 (4,5), side populations (6,7), PKH26 (8), ALDH1 (9,10), and the promoter reporter assays of hTERT (11)

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“…In fact, it is known that proteasome localizes to centrosomes/spindle poles and functions for cell homeostasis in many mammalian cells (25,26,28). In addition, some proteasome components are known to segregate asymmetrically during mitosis in T lymphocytes (29) and human pancreatic cancer cells (30). Thus, we believe that the ubiquitin-proteasome system may largely contribute to the reliable establishment of ACD.…”

Section: Discussionmentioning

confidence: 90%

Trim32 Facilitates Degradation of MYCN on Spindle Poles and Induces Asymmetric Cell Division in Human Neuroblastoma Cells

Izumi

Kaneko

2014

Cancer Research

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Asymmetric cell division (ACD) is a physiologic process during development and tissue homeostasis. ACD produces two unequal daughter cells: one has stem/progenitor cell activity and the other has potential for differentiation. Recent studies showed that misregulation of the balance between self-renewal and differentiation by ACD may lead to tumorigenesis in Drosophila neuroblasts. However, it is still largely unknown whether human cancer stem-like cells exhibit ACD or not. Here, using human neuroblastoma cells as an ACD model, we found that MYCN accumulates at spindle poles by GSK-3b phosphorylation during mitosis. In parallel, the ACD-related ubiquitin ligase Trim32 was recruited to spindle poles by CDK1/cyclin B-mediated phosphorylation. Trim32 interacted with MYCN at spindle poles during mitosis, facilitating proteasomal degradation of MYCN at spindle poles and inducing ACD. Trim32 also suppressed sphere formation of neuroblastoma-initiating cells, suggesting that the mechanisms of ACD produce differentiated neuroblastoma cells that will eventually die. Thus, Trim32 is a positive regulator of ACD that acts against MYCN and should be considered as a tumor-suppressor candidate. Our findings offer novel insights into the mechanisms of ACD and clarify its contributions to human tumorigenesis. Cancer Res; 74(19); 5620-30. Ó2014 AACR.

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Identification of Pancreatic Cancer Stem Cells and Selective Toxicity of Chemotherapeutic Agents

Cited by 113 publications

References 53 publications

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity

Trim32 Facilitates Degradation of MYCN on Spindle Poles and Induces Asymmetric Cell Division in Human Neuroblastoma Cells

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