Tumor Dormancy: Death and Resurrection of Cancer As Seen through Transgenic Mouse Models

Felsher, Dean W.

doi:10.4161/cc.5.16.3111

Cited by 27 publications

(23 citation statements)

References 28 publications

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“…The tactic has been to use transgenic mouse models with a conditional oncogene. Mouse models using the Tet system and/or chimeric gene products that could be activated in an on/off fashion are the two most common approaches (Giuriato et al 2004;Arvanitis and Felsher 2005;Felsher 2006). Many investigators have focused on MYC.…”

Section: Myc-induced Tumors Are Oncogene Addictedmentioning

confidence: 99%

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Gabay

Felsher

2014

Cold Spring Harbor Perspectives in Medicine

669

572

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The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cellintrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.

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Section: Myc-induced Tumors Are Oncogene Addictedmentioning

confidence: 99%

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Gabay

Felsher

2014

Cold Spring Harbor Perspectives in Medicine

669

572

View full text Add to dashboard Cite

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“…Because the majority of standard cytotoxics target rapidly dividing cells, cells that are in a state of growth arrest are immune to these therapies (131,132). Adhesion molecules including beta-integrins, VLA-4, and fibronectin have demonstrated that a reversible drug-resistant phenotype can be conferred upon epithelial tumors when these molecules are engaged (79,80,133).…”

Section: Targets For Therapymentioning

confidence: 99%

Structure and function of the solid tumor niche

Pedersen¹

2012

Front Biosci

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Although the hematopoietic stem cell (HSC) niche has been an active area of study, the concept of the bone marrow microenvironment (BMM) harboring a niche for solid metastatic tumor cells has only recently been considered. The HSC niche and microenvironment that is thought to constitute the solid tumor niche share many of the same structural and functional components, suggesting the possibility that the HSC and tumor niche are one in the same. The osteoblast is a critical component for each of these niches, and is important for regulating cellular processes such homing and migration, growth and survival, and quiescence and dormancy. Current understanding of the HSC niche may provide more insight to better defining the solid tumor niche. As role of the niche in regulating these processes is better understood, new insights to the role of the BMM in metastatic disease may be gained, and provide more potential targets for therapy. Keywordsniche; bone marrow microenvironment; hematopoietic stem cell; metastasis; disseminated tumor cell INTRODUCTIONIn 1889, Stephen Paget observed distinct metastatic patterns of 735 breast cancer patients. He found that breast cancer had a high propensity to spread to certain secondary sites, such as the marrow, while growth in other secondary sites was less common. This led him to famously state that metastatic cells, or "seeds", must fall on "congenial soil" (1). Paget was among the first to propose that the bone marrow must have specific factors conducive to metastatic growth. The concept of a specialized cellular "niche" was then proposed in 1978 by Richard Schofield when he observed that parenchymal cells in association with a stem cell can affect and determine stem cell behavior (2). Today, the concept of a stem cell niche is better understood, yet remains an active area of investigation (3)(4)(5). Likewise, the microenvironment of secondary growth and metastasis in epithelial tumors is a rapidly expanding field of research, but only recently has this microenvironment been considered in the context of a solid tumor niche (6). Primary tumors are known to interact with a diverse population of non-malignant cells, forming a tumor ecosystem (7). This ecosystem interaction is also observed in the bone marrow, a secondary site in which many types of metastatic tumor cells take up residence. This bone marrow ecosystem plays a significant role in regulating the activity of metastatic tumor cells (8), similar to the way the hematopoietic stem cell niche regulates stem cell activity. In this review, we will discuss the regulatory factors of the bone marrow microenvironment (BMM) that potentially comprise a niche for metastatic solid tumor cells. NIH Public Access Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2013 March 12.Published in final edited form as:Front Biosci (Schol Ed). ; 4: 1-15. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The HSC nicheInteractions between hematopoietic stem cells (HSCs) and their bone marrow...

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“…The altered milieu characterized by the dysregulated cytokines, enhanced proteolysis, hypoxia, phagocytosis of apoptotic tumor cells and Fc-receptor cross-linking all result in ensuing immunosuppression [9,[31][32][33][34] which sets the stage for escape.…”

Section: What Maintains the CI Equilibrium?mentioning

confidence: 99%

“…Holding the disease in this phase means stopping the progression, preventing the metastasis and thus converting the cancer from the deadly into a chronic disease. So far, the observations in patients of MRD suggest that the disease is more resistant to elimination during this phase as the cells are in a nondividing state [52][53][54][55]. As the immune system is not working it's full, boosting up of our immune machinery during this phase itself may help in eliminating the tumor or at least preventing its subsequent escape.…”

Section: Identification Of the Equilibrium Phase -The Real Challenge!mentioning

confidence: 99%

Cancer-Immune Equilibrium: Questions Unanswered

Bhatia

Kumar

2011

Cancer Microenvironment

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Cancer-immune (CI) equilibrium constitutes an important component of the cancer immunoediting theory. It is defined as a period during which our immune system and cancer live in harmony in the body. The immune system, though not able to completely eliminate the cancer, doesn't allow it to progress or metastasize further. Mechanisms of this phase are poorly understood because this phase is difficult to identify even by the most modern detection methods. Till now, the work done on the equilibrium phase of cancer, suggests promising improvements in cancer therapy if the disease could be withheld in this phase. However, there are many queries which remain to be addressed about this interesting yet unresolved phase of cancer immunity.

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Tumor Dormancy: Death and Resurrection of Cancer As Seen through Transgenic Mouse Models

Cited by 27 publications

References 28 publications

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Structure and function of the solid tumor niche

Cancer-Immune Equilibrium: Questions Unanswered

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