Lung cancer stem cells: tools and targets to fight lung cancer

Eramo, Adriana; Haas, Tobias L.; Maria, Ruggero De

doi:10.1038/onc.2010.207

Cited by 131 publications

(148 citation statements)

References 101 publications

(121 reference statements)

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“…Similarly, stem-like cancer cells have been reported in human cancers of the prostate [87][88][89][90][91][92][93][94][95][96][97][98][99][100], lung [101][102][103][104][105][106][107][108][109][110][111], and many other organs (liver, pancreas, kidney, bladder, ovary, etc). In prostate cancer, tumor-initiating cells have been identified in xenografts in CD44 + [90,96], CD44 + α2β1 + [91], TRA-1-60 + CD151 + CD166 + [99], and ALDH + [97,98] populations as well as in SP [87] and holoclones [94].…”

Section: Csc Heterogeneitymentioning

confidence: 99%

“…For example, although LSC activity has been detected in several cellular compartments, the most tumorigenic subpopulation is still in undifferentiated Lin -CD34 + CD38 -cells, which can develop into more mature, less tumorigenic cells [112,113,115]. Likewise, in marker-independent sphere-(e.g., neurosphere, mammosphere, colonosphere, prostasphere, etc) formation assays, it has been repeatedly demonstrated that a single (undifferentiated) tumor cell can generate a sphere that contains multiple types of lineage-differentiated cells [49,61,66,76,80,90,95,100,106]. CD133 + colon CSCs can grow exponentially for more than a year as undifferentiated tumor spheres in vitro but, upon transplantation in vivo, they can generate tumors that histologically recapitulate the morphological and antigenic pattern of the original tumor [76].…”

Section: Intrinsic and Induced Plasticity In Csc Progenymentioning

confidence: 99%

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Understanding cancer stem cell heterogeneity and plasticity

2012

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Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

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Section: Csc Heterogeneitymentioning

confidence: 99%

Section: Intrinsic and Induced Plasticity In Csc Progenymentioning

confidence: 99%

Understanding cancer stem cell heterogeneity and plasticity

2012

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“…1,2 There is increasing evidence that cancer stem cells (CSCs) have a key role in drug resistance, tumor progression and metastasis in multiple tumor types, including lung cancer. 3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. [4][5][6][7][8][9] Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies.…”

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confidence: 99%

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

et al. 2014

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Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-X L is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-X L inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-X L . In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/ slow-proliferating LCSC strongly depend on Bcl-X L for their survival and indicate Bcl-X L inhibition as a potential therapeutic avenue in NSCLC. Cell Death and Differentiation (2014) 21, 1877-1888; doi:10.1038/cdd.2014.105; published online 18 July 2014Lung cancer is the leading cause of cancer-related death in men and is expected to become the main cause of cancer death for women in the near future. 1,2 There is increasing evidence that cancer stem cells (CSCs) have a key role in drug resistance, tumor progression and metastasis in multiple tumor types, including lung cancer. 3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. 4-9 Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies. 10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-X L and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance. 11 Inhibition of anti-apoptotic Bcl-2 family members has been for long time regarded as a promising strategy to induce cancer cell death through approaches of increasing specificity. BH3 mimetics such as ABT-737, the related orally available ABT-263 (navitoclax) and the recently developed Bcl-2-selective inhibitor ABT-199 have been shown to exert an antitumor effect in preclinical and clinical settings either as single agents or in combination with conventional or targeted drugs. 12 Recently, a new role for Bcl-2 has emerged in acute myeloid leukemia (AML), whe...

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“…Growing evidence shows a connection between epigenetic abnormalities in cancer and subpopulations with stem cells-like traits [14][15][16]. CSCs have been identified and characterized by the expression of markers, including CD133, CD44, aldehyde dehydrogenase (ALDH), side population [17][18][19][20][21], and by their cellular traits such as morphology, colony formation ability, and other aggressive behaviors [22]. Nowadays, several studies provide strong evidence for the existence of a cellular subpopulation with stem-like traits also in NSCLC [20,22,23], where the presence of these cells predicts a worse prognosis for patients [24].…”

Section: Introductionmentioning

confidence: 99%

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

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Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.

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Lung cancer stem cells: tools and targets to fight lung cancer

Cited by 131 publications

References 101 publications

Understanding cancer stem cell heterogeneity and plasticity

Understanding cancer stem cell heterogeneity and plasticity

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

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