The Problem of Cancer Dormancy: Understanding the Basic Mechanisms and Identifying Therapeutic Opportunities

Aguirre‐Ghiso, Julio A.

doi:10.4161/cc.5.16.3165

Cited by 53 publications

(40 citation statements)

References 50 publications

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“…The independence of cell death induced by COPI inhibition from cell-cycle progression is indicated further by the observation that cells transfected with COPZ1 siRNA die through apoptosis, without undergoing abnormal mitosis (mitotic catastrophe), the common cause of death in cells treated with conventional anticancer drugs (26,40). Chemotherapy-resistant nondividing tumor cells include the damaged/senescent cell population that secretes mitogenic, antiapoptotic, angiogenic, and proteolytic factors (6), as well as resting tumor stem cells (8) and dormant cells that can survive for years before reentering the cell cycle (7). The failure to destroy resting and dormant tumor cells is a general cause of tumor relapse after the initial remission.…”

Section: Discussionmentioning

confidence: 99%

“…Most existing anticancer drugs act either on DNA or on protein targets involved in cell proliferation. Such drugs kill proliferating tumor cells but are ineffective against the nondividing tumor cell population, which includes growtharrested cells that secrete various tumor-promoting factors (6), dormant cells capable of eventual reentry into cell cycle (7), and resting tumor stem cells (8). Proliferating and nondividing tumor cells, however, share common genetic and epigenetic changes, and some of the tumor-specific targets in proliferating cells also may be required for the survival of nondividing tumor cells.…”

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confidence: 99%

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Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit ζ2 renders tumor cells dependent on its paralogous gene COPZ1

Shtutman

Baig²,

Levina³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Anticancer drugs are effective against tumors that depend on the molecular target of the drug. Known targets of cytotoxic anticancer drugs are involved in cell proliferation; drugs acting on such targets are ineffective against nonproliferating tumor cells, survival of which leads to eventual therapy failure. Function-based genomic screening identified the coatomer protein complex ζ1 (COPZ1) gene as essential for different tumor cell types but not for normal cells. COPZ1 encodes a subunit of coatomer protein complex 1 (COPI) involved in intracellular traffic and autophagy. The knockdown of COPZ1, but not of COPZ2 encoding isoform coatomer protein complex ζ2, caused Golgi apparatus collapse, blocked autophagy, and induced apoptosis in both proliferating and nondividing tumor cells. In contrast, inhibition of normal cell growth required simultaneous knockdown of both COPZ1 and COPZ2. COPZ2 (but not COPZ1) was down-regulated in the majority of tumor cell lines and in clinical samples of different cancer types. Reexpression of COPZ2 protected tumor cells from killing by COPZ1 knockdown, indicating that tumor cell dependence on COPZ1 is the result of COPZ2 silencing. COPZ2 displays no tumor-suppressive activities, but it harbors microRNA 152, which is silenced in tumor cells concurrently with COPZ2 and acts as a tumor suppressor in vitro and in vivo. Silencing of microRNA 152 in different cancers and the ensuing down-regulation of its host gene COPZ2 offer a therapeutic opportunity for proliferation-independent selective killing of tumor cells by COPZ1-targeting agents.cancer targets | genetic suppressor elements

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit ζ2 renders tumor cells dependent on its paralogous gene COPZ1

Shtutman

Baig²,

Levina³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…This is a daunting clinical problem, and the frequent re-emergence of tumors occurs even after treatment because of prolonged dormancy [37]. In ovarian cancer cells, autophagy is upregulated by the tumor suppressor aplasia Ras homolog member I (ARHI), which promotes in vivo survival of dormant cells in tumor microenvironments [2,38].…”

Section: Autophagy and Metastasismentioning

confidence: 99%

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

Panda

Mukhopadhyay

Das

et al. 2015

Seminars in Cell & Developmental Biology

127

115

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“…Conversion to an actively proliferating population could also occur in response to changes in the host tissue (eg, injury, change in hormonal status, ageing, initiation of angiogenesis) or the development of a suitable niche. 163 Failure to distinguish bona fide metastases from inert disseminated cells has important implications. Current medical practice is to eliminate all risk.…”

Section: -158mentioning

confidence: 99%

Metastasis: recent discoveries and novel treatment strategies

Eccles¹,

Welch²

2007

The Lancet

663

523

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Most cancer deaths are due to the development of metastases, hence the most important improvements in morbidity and mortality will result from prevention (or elimination) of such disseminated disease. Some would argue that treatments directed against metastasis are too late because cells have already escaped from the primary tumour. Such an assertion runs contrary to the significant but (for many common adult cancers) fairly modest improvements in survival following the use of adjuvant radiation and chemotherapy designed to eliminate disseminated cells after surgical removal of the primary tumour. Nonetheless, the debate raises important issues concerning the accurate early identification of clonogenic, metastatic cells, the discovery of novel, tractable targets for therapy, and the monitoring of minimal residual disease. We focus on recent findings regarding intrinsic and extrinsic molecular mechanisms controlling metastasis that determine how, when, and where cancers metastasise, and their implications for patient management in the 21st century.

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The Problem of Cancer Dormancy: Understanding the Basic Mechanisms and Identifying Therapeutic Opportunities

Cited by 53 publications

References 50 publications

Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit ζ2 renders tumor cells dependent on its paralogous gene COPZ1

Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit ζ2 renders tumor cells dependent on its paralogous gene COPZ1

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

Metastasis: recent discoveries and novel treatment strategies

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