A Model of Human Tumor Dormancy: An Angiogenic Switch From the Nonangiogenic Phenotype

Naumov, George N.; Bender, Elise; Zurakowski, David; Kang, Soo Young; Sampson, David A.; Flynn, Evelyn; Watnick, Randolph S.; Straume, Oddbjørn; Akslen, Lars A.; Folkman, Judah; Almog, Nava

doi:10.1093/jnci/djj068

Cited by 373 publications

(317 citation statements)

References 29 publications

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“…VEGF upregulation is a trigger for initiation of angiogenesis from dormant metastases and the angiogenesis inhibitor thrombospondin 1 might inhibit VEGF activity to promote dormancy 124 . Hypoxia, on the other hand will increase HIF1 activity to upregulate VEGF while downregulating thrombospondin, to create a pro-angiogenic environment 117 .…”

Section: Hypoxia and Angiogenesismentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Hypoxia and Angiogenesismentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Thrombospondin 1 is a large heterotrimer whose expression increases in most aged cells and tissues (Naumov et al, 2006). The negative effects of TSP1 on endothelial cell function have resulted in great interest in this protein in tumour angiogenesis and progression.…”

Section: Matricellular Proteinsmentioning

confidence: 99%

“…The negative effects of TSP1 on endothelial cell function have resulted in great interest in this protein in tumour angiogenesis and progression. In many cancers, TSP1's presence is associated with a non-angiogenic phenotype and tumour regression; the absence of TSP1 expression is correlated with an angiogenic switch and metastases (Naumov et al, 2006). Thrombospondin 1 inhibits angiogenesis by blocking growth factor-mediated angiogenic functions such as proliferation and migration as well as by enhancing apoptosis in activated endothelial cells (Colombel et al, 2005).…”

Section: Matricellular Proteinsmentioning

confidence: 99%

Extracellular influences on tumour angiogenesis in the aged host

2008

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Whether tumours are epithelial or non-epithelial in origin, it is generally accepted that once they reach a certain size all solid tumours are dependent upon a vascular supply to provide nutrients. Accordingly, there is great interest in how the extracellular environment enhances or inhibits vascular growth. In this minireview, we will examine key extracellular components, their changes with ageing, and discuss how these alterations may influence the subsequent development of tumour vasculature in the aged host. Because of the tight correlation between advanced age and development of prostate cancer, we will use prostate cancer as the model throughout this review.

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“…During the dormant state, tumor cells survive in the host tissues remaining confined in a low proliferating or quiescent state, resisting to drugs and immune attacks, until being recruited into a high proliferation compartment by either genetic or epigenetic changes. Dormancy may be sustained by limited blood supply; this condition of low oxygen and reduced nutrients determines an absolute increase of tumor cells number very close to zero, since the number of dividing cells may equate the number of dying cells [3,4]. It is important to remember that many of the mechanisms proposed to explain dormancy have been identified using experimental models, although all are very plausible, up to now are not completely confirmed in tumor-bearing patients [1].…”

Section: Introductionmentioning

confidence: 99%

The acidic microenvironment as a possible niche of dormant tumor cells

Peppicelli

Andreucci

Ruzzolini

et al. 2017

Cell. Mol. Life Sci.

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A Model of Human Tumor Dormancy: An Angiogenic Switch From the Nonangiogenic Phenotype

Abstract: This model provides a conceptual framework and a reproducible in vivo system to study unresolved central questions in cancer biology regarding the initiation, reversibility, and molecular regulation of the timing of the angiogenic switch.

Cited by 373 publications

References 29 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Extracellular influences on tumour angiogenesis in the aged host

The acidic microenvironment as a possible niche of dormant tumor cells

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