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Tumor cell dormancy induced by p38(SAPK) and ER-stress signaling - An adaptive advantage for metastatic cells?

Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, NY 12144-3456, USA.
Cancer biology & therapy (Impact Factor: 3.63). 08/2006; 5(7):729-35. DOI: 10.4161/cbt.5.7.2968
Source: PubMed

ABSTRACT The mechanisms that determine whether a tumor cell that has disseminated to a secondary site will resume growth immediately, die or enter a state of dormancy are poorly understood. Although tumor dormancy represents a common clinical finding, studying the mechanisms behind this stage of tumor progression has been challenging. Furthermore, it is thought that dormant tumor cells are refractory to chemotherapy due to their lack of proliferation. However, whether this is the only reason for their chemo-resistance remains to be proven. In this review we summarize recent findings that provide a mechanistic explanation about how stress signaling through the p38(SAPK) pathway and ER-stress signaling may coordinate the induction of growth arrest and drug-resistance in a model of squamous carcinoma dormancy. We further discuss how dormant tumor cells may enter this stage to adapt to strenuous conditions that do not favor immediate growth after dissemination. Finally, we propose that this response may recapitulate an evolutionarily conserved program of life-span extension through adaptation and tolerance to stress.

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    • "p38 is activated through phosphorylation at the Thr180-Gly-Tyr182 motif by MKK3, MKK4, and MKK6 [13]. Phosphorylated p38 activates a wide range of substrates that include transcription factors, protein kinases, and nuclear proteins, leading to diverse responses such as inflammatory responses, cell differentiation, cell-cycle arrest, apoptosis, senescence, cytokine production, and regulation of RNA splicing [14], [15]. The specific inhibitors, inactivating p38 by directly or indirectly acting on ATP-binding pocket [16], have been reported that could enhance the treatment effect of all-trans-retinoic acid in acute promyelocytic leukemia cell [17], arsenic trioxide in chronic myeloid leukemia cell [18] and bortezomib in multiple myeloma cell [19]. "
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    • "Alleviation of ER stress is achieved by the unfolded protein response (UPR). One arm of the UPR induces the activities of transcriptional factors, such as Xbp1, allowing survival signaling without affecting proliferation (Carrasco et al., 2007; Koong et al., 2006; Ranganathan et al., 2006a; Romero-Ramirez et al., 2004). The other arm consists in the attenuation of protein synthesis via Ser 52 phosphorylation of the ␣ subunit of the translation initiation factor eIF2 (Kaufman, 2002), thus preventing cyclin D1 expression and inducing arrest in G0/G1 (Brewer et al., 1999). "
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    • "These steps are usually followed by extravasation into the surrounding tissue, survival in the foreign microenvironment, proliferation, and induction of angiogenesis (Figure 1). It has become apparent that the vast majority of tumor cells within the primary tumor and also the disseminated tumor cells will not form distant metastases , either because they die or remain dormant [4]. The dormancy phenomenon probably explains what is seen in the clinic in which some cancer patients remain free of clinical evidence of metastatic disease for years or even decades after primary tumor resection, and after this prolonged period of time these patients show signs of tumor relapse. "
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