scholarly journals Pituitary tumors contain a side population with tumor stem cell-associated characteristics

2015 ◽  
Vol 22 (4) ◽  
pp. 481-504 ◽  
Author(s):  
Freya Mertens ◽  
Lies Gremeaux ◽  
Jianghai Chen ◽  
Qiuli Fu ◽  
Christophe Willems ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Side Population ◽  
Pituitary Tumors ◽  
Stem Cell Marker ◽  
Tumor Stem Cell ◽  
Tumor Pathogenesis

Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express ‘tumor stemness’ markers and signaling pathways, including epithelial–mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self-renewing sphere-forming cells, considered to be a property of TSCs. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP ‘main population’. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFβ had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2−/−) mice that bear prolactinomas contain more pSP, Sox2+, and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. The present study adds new elements to the unraveling of pituitary tumor pathogenesis and may lead to the identification of new therapeutic targets.

scholarly journals Side Population Does Not Define Stem Cell-Like Cancer Cells in the Adrenocortical Carcinoma Cell Line NCI h295R

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1314-1322 ◽  
Author(s):  
Urs D. Lichtenauer ◽  
Igor Shapiro ◽  
Klaus Geiger ◽  
Marcus Quinkler ◽  
Martin Fassnacht ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Cell Population ◽  
Side Population ◽  
Primary Cultures ◽  
Regulatory Protein ◽  
Cytotoxic Agents ◽  
Tumor Stem Cell ◽  
Proliferative Potential ◽  
Tumor Entities

Recent evidence suggests the existence of a stem cell-like subpopulation of cells in hematological and solid tumor entities, which determine the malignant phenotype of a given tumor through their proliferative potential and chemotherapy resistance. A recently used technique for the isolation of this cell population is through exclusion of the vital dye Hoechst 33342, which defines the so-called side population (SP). Herein we demonstrate the presence of SP cells in a variety of adrenal specimens, including primary cultures of human adrenocortical tumors and normal adrenal glands as well as established human and murine adrenocortical cancer cell lines by fluorescence-activated cell sorter analysis and confocal microscopy. On a functional level, SP cells from the human adrenocortical tumor cell line NCI h295R revealed an expression pattern consistent with a less differentiated phenotype, including lower expression of steroidogenic enzymes such as steroid acute regulatory protein (StAR) and side-chain cleavage enzyme (P450scc) in comparison with non-SP cells. However, proliferation between SP and non-SP cells did not differ (105.6 ± 18.1 vs. 100.0 ± 3.5%). Furthermore, re-sorting and tracing experiments revealed the capacity for both cell types to give rise to the original SP- and non-SP-containing cell population. Similarly to the baseline growth kinetics, no survival benefit was evident in SP cells after treatment with cytotoxic agents commonly used in adrenocortical carcinomas. Taken together, these findings provide evidence that Hoechst dye exclusion, in contrast to what has been reported for other tumor entities, is not a major tumor stem cell defining marker in adrenocortical NCI h295R tumor cells.

scholarly journals p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

2014 ◽  
Vol 21 (3) ◽  
pp. 395-404 ◽  
Author(s):  
Tomoko Sekiya ◽  
Marcello D Bronstein ◽  
Katiuscia Benfini ◽  
Viviane C Longuini ◽  
Raquel S Jallad ◽  
...  
Keyword(s):  
Cell Line ◽  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
In Vitro Study ◽  
Mouse Cell ◽  
Endocrine Tumor ◽  
Endocrine Tumors ◽  
Parathyroid Adenomas ◽  
Acth Secreting

Abstract Germline mutations in p27kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

scholarly journals Pituitary tumors contain a side population with tumor stem cell-associated characteristics

2016 ◽  
Author(s):  
Freya Mertens ◽  
Lies Gremeaux ◽  
Jianghai Chen ◽  
Qiuli Fu ◽  
Christophe Williems ◽  
...  
Keyword(s):  
Stem Cell ◽  
Side Population ◽  
Pituitary Tumors ◽  
Tumor Stem Cell

scholarly journals The side population phenomenon enriches for designated adrenocortical progenitor cells in mice

2012 ◽  
Vol 215 (3) ◽  
pp. 383-391
Author(s):  
Urs Lichtenauer ◽  
Igor Shapiro ◽  
Simone Sackmann ◽  
Jacques Drouin ◽  
Jürgen Scheele ◽  
...  
Keyword(s):  
Stem Cell ◽  
Side Population ◽  
Indirect Evidence ◽  
Stem Cell Marker ◽  
Wild Type ◽  
Acth Treatment ◽  
Cell Arrest

Somatic adrenal stem cells are believed to reside in the periphery of the adrenal cortex throughout life for organ maintenance. Herein, we used the side population (SP) phenomenon to enrich for these progenitors, which made up to 0.01–0.64% of the total cell count. Microarray analysis revealed an expression profile of SP cells, which clearly differed from that of non-SP cells. However, a promising adrenal specific stem cell marker could not be identified.In vitro, SP cells could be maintained in long-term culture, whereas non-SP cells did not proliferate. After 4 weeks of culturing, immunohistochemistry revealed the expression of steroidogenic enzymes such as 3β-HSD, StAR, and P450SCC, suggesting spontaneous differentiation. Interestingly, the quantity of SP cells was significantly diminished inPbx1haploinsufficient mice, suggesting a stem cell deficit. By contrast, the subcapsular zone of ACTH-deficientTpit−/−mice was significantly wider compared with wild-type adrenals (Tpit−/−259±10.7 vsTpit+/−100±12.3%;P<0.01). Accordingly, the number of SP cells in these mice was significantly higher (Tpit−/−0.45±0.16 vsTpit+/−0.13±0.04%;P<0.004). ACTH treatment of these animals reverted the subcapsular zone width and the SP fraction back to normal (130±10.2%;P=0.33 and 0.09%), providing indirect evidence for a stem cell ‘arrest’ inTpit−/−mice and the role of ACTH in adrenocortical stem cell modulation and differentiation.

scholarly journals Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1303
Author(s):  
Rizwan Ali ◽  
Hajar Al Zahrani ◽  
Tlili Barhoumi ◽  
Alshaimaa Alhallaj ◽  
Abdullah Mashhour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells’ expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

Characterization of a pituitary-tumor-derived cell line, TtT/GF, that expresses Hoechst efflux ABC transporter subfamily G2 and stem cell antigen 1

2013 ◽  
Vol 354 (2) ◽  
pp. 563-572 ◽  
Author(s):  
Hideo Mitsuishi ◽  
Takako Kato ◽  
Mo Chen ◽  
Li-Yi Cai ◽  
Hideji Yako ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Abc Transporter ◽  
Pituitary Tumor ◽  
Cell Antigen

scholarly journals In Vitro Cell Motility as a Potential Mesenchymal Stem Cell Marker for Multipotency

2014 ◽  
Vol 4 (1) ◽  
pp. 84-90 ◽  
Author(s):  
Alessandro Bertolo ◽  
Armin Gemperli ◽  
Marco Gruber ◽  
Benjamin Gantenbein ◽  
Martin Baur ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Motility ◽  
Stem Cell Marker ◽  
Cell Marker

scholarly journals Maintenance of high levels of pluripotent hematopoietic stem cells in vitro: effect of stromal cells and c-kit

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 365-372 ◽  
Author(s):  
JP Wineman ◽  
S Nishikawa ◽  
CE Muller-Sieburg
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Line ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Stromal Cell Line ◽  
Cell Maintenance

We show here that mouse pluripotent hematopoietic stem cells can be maintained in vitro on stroma for at least 3 weeks at levels close to those found in bone marrow. The extent of stem cell maintenance is affected by the nature of the stromal cells. The stromal cell line S17 supported stem cells significantly better than heterogeneous, primary stromal layers or the stromal cell line Strofl-1. Stem cells cultured on S17 repopulated all hematopoietic lineages in marrow-ablated hosts for at least 10 months, indicating that this culture system maintained primitive stem cells with extensive proliferative capacity. Furthermore, we demonstrate that, while pluripotent stem cells express c-kit, this receptor appears to play only a minor role in stem cell maintenance in vitro. The addition of an antibody that blocks the interaction of c-kit with its ligand essentially abrogated myelopoiesis in cultures. However, the level of stem cells in antibody-treated cultures was similar to that found in untreated cultures. Thus, it seems likely that the maintenance of primitive stem cells in vitro depends on yet unidentified stromal cell-derived factor(s).

scholarly journals PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Population ◽  
Side Population ◽  
Chemotherapeutic Agents ◽  
Stem Cell Population ◽  
Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

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