The cancer stem-cell signaling network and resistance to therapy

Carnero, Amancio; García-Mayea, Yoelsis; Mir, Cristina; Lorente, Juan; Rubio, Isabel T.; Lleonart, Matilde E.

doi:10.1016/j.ctrv.2016.07.001

Cited by 126 publications

(123 citation statements)

References 96 publications

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“…This is consistent with other works describing that PIM phosphorylates and enhances OCT4 and MYC, which also contributes to the reprogramming of tumor cells852. Furthermore, other PIM-dependent pathways promoting the self-renewal of stem cells have been reported53545556. PIM kinases might influence self-renewal and reprogramming through direct phosphorylation of BCRP/ABCG2, a putative stem cell marker, which may be involved in multiple drug resistance57.…”

Section: Discussionsupporting

confidence: 91%

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

Jiménez-García

Lucena-Cacace

Robles‐Frías

et al. 2016

Sci Rep

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The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis. We found an increase in alterations of sexual organs and hyperplasia in the transgenic mice correlating with inflammation. We also found that PIM1/2 are overexpressed in a subset of human male germ cells and prostate tumors correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression is a common feature of male reproductive organs tumors, which provoke tissue alterations and a large inflammatory response that may act synergistically during the process of tumorigenesis. There is also a correlation with markers of cancer stem cells, which may contribute to the therapy resistance found in tumors overexpressing PIM kinases.The Proviral Insertion site in Moloney murine leukemia virus proteins (PIM) are a highly evolutionarily conserved family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2 and PIM3). These proteins are regulated primarily through transcription and stability by pathways that are controlled by JAK/STAT transcription factors 1,2 , cytokines, and growth factors involved in hematopoiesis, such as interleukins, GM-CSF and G-CSF 3,4 . In addition, nuclear factor-κ B, Jak-signal transducer and activator of transcription (STAT), ETS-related gene and hypoxia-inducible factor-1α are the primary pathways that induce PIM1 upregulation [5][6][7][8] . Furthermore, the stability and function of PIM kinases depend on their interaction with heat shock protein (Hsp) 90 9,10 , a chaperone involved in the folding and stabilization of different molecules. Hsp90 has been shown to not only to protect from ubiquitin-dependent proteasomal degradation but has also been shown to maintain the proper conformation of PIM proteins 10 . The downstream targets of PIM1 signaling are typically regulated by direct phosphorylation by PIM1. Thus far, approximately 30 substrates have been shown to interact with and be phosphorylated by PIM1. Through phosphorylation of target proteins, PIM1 plays essential roles in the regulation of the cell cycle, cell proliferation, anti-apoptosis, multiple drug resistance, chromatin remodeling, protein translation, energy metabolism, and the stress response [11][12][13] . It has been suggested that PIM family members are weak oncogenes that can contribute to tumorigenesis by selectively enhancing tumorigenic properties 1,2 . However, PIM family members have also been shown to increase the capacity of other genes or chemical carcinogens to induce tumors [14][15][16] . The magnitude of the effect varies depending on...

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Section: Discussionsupporting

confidence: 91%

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

Jiménez-García

Lucena-Cacace

Robles‐Frías

et al. 2016

Sci Rep

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“…506,507 IL-1 stimulates the secretion of PGE2 via autocrine signaling, which ultimately activates β-catenin signaling in cancer cells in a paracrine manner and transforms cancer cells into CSCs. 508 In the ECM, bone mesenchymal stem cells activate the NF-κB pathway and induce a CSC phenotype by secreting a variety of cytokines and chemokines, such as CXCL12, CXCL7, and IL-6/IL-8. 509 The interaction between MDSCs and CSCs via IL-6/STAT3 and Notch signaling is critical to the progression of breast cancer.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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“…Moreover, parthenolide was the first small molecule shown to selectively kill cancer stem cells, while leaving normal stem cells intact [524,534]. This is of enormous therapeutic importance, since the presence of cancer stem cells is considered as one of the main reasons underlying chemotherapy resistance and tumor relapse due to their capacity of self-renewal and differentiation into multiple cell types [535,536]. The mechanism behind parthenolide selectivity towards cancer stem cells is not completely understood, but it is believed that the reason lies in its ability to target multiple major pathways required for cancer stem cell survival and self-renewal, such as MAPK, JAK/STAT, PI3K and NF-κB signaling [524,537].…”

Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

156

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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The cancer stem-cell signaling network and resistance to therapy

Cited by 126 publications

References 96 publications

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

Targeting cancer stem cell pathways for cancer therapy

Mechanisms of Chromosome Congression during Mitosis

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