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Review
. 2006 Aug;5(16):1799-807.
doi: 10.4161/cc.5.16.3109. Epub 2006 Aug 15.

Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy

Aparna C Ranganathan  1 , Alejandro P Adam, Julio A Aguirre-Ghiso
Affiliations
Review

Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy

Aparna C Ranganathan et al. Cell Cycle. 2006 Aug.

Abstract

Cancer dormancy is a poorly understood stage of cancer progression. However, the ability to control this step of the disease offers novel therapeutic opportunities. Here we summarize recent findings that implicate the extracellular matrix and adhesion receptor signaling in the escape or induction of tumor dormancy. We further review evidence suggesting that imbalances in the activity ratio of ERK to p38 signaling may determine the fate (i. e. , tumorigenicity vs. dormancy) of different carcinoma cells. Special attention is placed on the mechanisms that p38 signaling regulates during the induction of dormancy and how modulation of these pathways may offer a therapeutic opportunity VSports手机版. We also review evidence for a novel drug-resistance mechanism in dormant tumor cells that when blocked may enable killing of dormant tumor cells. Finally, we explore the notion that dormancy of tumor cells may be the result of a selective adaptive response that allows disseminated tumor cells to pause their growth and cope with stress signaling imposed by dissemination and/or treatment until growth can be restored. .

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Figures

Figure 1
Figure 1
(A) A graphical representation of the progression of a tumor mass in patients. Over long periods (years) the accumulation of genetic and epigenetic changes that confer growth advantages lead to cell transformation and tumor development. Upon diagnosis, treatment involves primary tumor resection and or adjuvant chemotherapy. Nevertheless, in situ or disseminated single growth arrested cells or small groups of cells lacking vascularization may persist undetected for months to decades. At any given moment, tumor cells may emerge from quiescence and/ or acquire angiogenic potential and resume uncontrolled proliferation in situ or in distant organs. (B) Schematic depiction of the HEp3 tumor dormancy model. Tumorigenic cells with high ERK and low p38 signaling (T-HEp3) can proliferate efficiently when inoculated in vivo. In contrast cells with high p38 and low ERK activity (dormant, D-HEp3) are unable to grow in vivo and hence form small nodules that contain tumor cells in a G0/G1 arrest and are dormant for months. However these cells can revert to a tumorigenic phenotype either spontaneously after prolonged passaging in vivo (R-HEp3) or following downregulation of p38 activity with a dominant negative p38α or with a p38 inhibitor (SB203850), all of which tip the balance towards ERK signaling.
Figure 2
Figure 2
Cell surface regulation of the ERK/p38 ratio as a determinant of tumor dormancy. (Left) In uPAR rich HEp3 cells, the uPA bound receptor, through a region requiring Ser-245, interacts frequently with the FN receptor α5β1-integrin leading to efficient assembly of FN fibrils. Further, this interaction results in the formation of a functional complex involving FAK and EGFR, leading to a strong activation of the Ras-ERK mitogenic signaling and inhibition of p38 signaling via inactivation of Cdc42. This results in a high ERK/p38 ratio that favors proliferation and promotes tumorigenicity. (Right) Down regulation of uPAR expression, blocking of integrin function or inhibition of FAK results in the disassembly of the complex and reduced ERK activation. Consequently this leads to the activation of Cdc42 and subsequent activation of p38 resulting in a low ERK/p38 ratio, which favors growth arrest and forces the tumor cells into dormancy.
Figure 3
Figure 3
Regulation of ER-stress by p38 and tumor dormancy. (A) Simplified overview of pathways of the UPR relevant to this review. ER-stress induces dissociation of BiP from PERK and IRE1 and their subsequent activation via trans-phosphorylation. IRE1 activation leads to the noncanonical splicing of XBP-1 mRNA, causing a frame-shift in the ORF resulting in a potent transcription factor. Active PERK phosphorylates eIF2α on Ser 51, inhibiting translation and causing G0/G1 arrest. Preferential translation of ATF4 mRNA by phospho-eIF2α also induces (along with XBP1) the expression of UPR genes. P = phospho-group. ERSE = ER stress response element. Dephosphorylation of eIF2α by GADD34-PP1 restores translation. (B) Activation of p38 signaling in HEp3 cells regulates a program that favors growth arrest and survival through the activation of an ER stress response. While p38-dependent activation of PERK-eIF2α pathway coordinates both growth arrest and survival signaling, upregulation of BiP expression inhibits Bax activation and promotes survival and drug resistance in dormant cells without affecting the dormancy of the tumor cells.
Figure 4
Figure 4
Potential mechanisms that may explain the dormancy of tumor cells. Disseminated cells are subject to strenuous conditions during the metastatic cascade. Tumor cells that are unable to cope with the stress induced by dissemination and/or an unfavorable milieu may pause growth but survive as isolated cells. Growth of these cells into a mass that remains avascular will result in dormancy as well. While single disseminated cells may enter dormancy through a growth arrest, dormancy of an avascular tumor mass results from the apoptotic rate balancing the proliferation rate. Although these mechanisms are different, they may share some regulatory pathways dependent on activation of p38 and/or metastasis suppressor genes that may become dominant in an unfavorable microenvironment. Spontaneous inhibition of these signals may interrupt dormancy and promote secondary growth.
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