PAS‐positive loops and networks as a prognostic indicator in cutaneous malignant melanoma

Thies, Anka; Mangold, Ulrich; Moll, Ingrid; Schumacher, Udo

doi:10.1002/path.988

Cited by 60 publications

(52 citation statements)

References 17 publications

(22 reference statements)

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“…7,14 These patterns stain only focally and weakly for collagen I and are structurally different from stromal host-derived fibrovascular septa. There is a strong association between the histological detection of vasculogenic mimicry patterns in primary uveal [15][16][17][18][19][20][21] and cutaneous 22,23 melanomas and subsequent death from metastasis, consistent with the in vitro observations that these patterns are generated exclusively by highly invasive tumor cells. 1,4 Although differences in gene expression between poorly invasive and highly invasive melanoma cells capable of generating vasculogenic mimicry patterns have been identified, 1,24,25 there are no reports of gene expression in tumor cells that have generated patterns.…”

supporting

confidence: 60%

Tumor Cell Plasticity in Uveal Melanoma

Folberg

Arbieva

Moses

et al. 2006

The American Journal of Pathology

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The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment. The term vasculogenic mimicry describes the formation of perfusion pathways in tumors by highly invasive, genetically deregulated tumor cells 1,2 : vasculogenic because, although these pathways do not form from preexisting vessels, they distribute plasma and may contain red blood cells and mimicry because the pathways are not blood vessels and merely mimic vascular function. In vasculogenic mimicry of the patterned matrix type, 3 highly invasive tumor cells form looping patterns rich in extracellular matrix (ECM) in three-dimensional (3D) culture conditions. 1 Highly invasive tumor cells do not generate these patterns when grown under monolayer conditions or on thin matrix, and poorly invasive tumor cells do not generate these patterns under any culture condition. 1,4 These looping patterns, termed the "fluid-conducting meshwork," 5 connect to endothelial cell-lined blood vessels 4,6 and conduct fluid in vitro 1,4 and in animal models of melanoma. 5,7,8 Vasculogenic mimicry patterns are composed of laminin, 5,9,10 collagen types IV 11 and VI, 12 fibronectin, 13 Pathology, Vol. 169, No. 4, October 2006 Copyright © American Society for Investigative Pathology DOI: 10.2353/ajpath.2006 1376 focally and weakly for collagen I and are structurally different from stromal host-derived fibrovascular septa. There is a strong association between the histological detection of vasculogenic mimicry patterns in primary uveal [15][16][17][18][19][20][21] and cutaneous 22,23 melanomas and subsequent death from metastasis, consistent with the in vitro observatio...

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supporting

confidence: 60%

Tumor Cell Plasticity in Uveal Melanoma

Folberg

Arbieva

Moses

et al. 2006

The American Journal of Pathology

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“…37 Although the specific functions that underlie VM remain unclear and at times controversial, VM is clearly associated with tumor aggressiveness, poor clinical outcome, and high risk of recurrence. 118,120,121 Furthermore, conventional antiangiogenic therapies, such as endostatin, have been ineffective at inhibiting VM. 122 The melanoma cells that form the patterned vascular channels characteristic of VM are highly invasive, multipotent cells that express primitive genes.…”

Section: How Primitive Melanoma Cells May Encourage 'Vasculogenic Mimmentioning

confidence: 99%

Melanoma stem cells: not rare, but well done

Girouard

Murphy

2011

Laboratory Investigation

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Since the identification of self-renewing cells in the hematopoietic system, stem cells have transformed the study of medicine. Cancer biologists have identified stem-like cells in multiple malignancies, including those of solid organs. This has led to the development of a stem cell theory of cancer, which purports that a subpopulation of self-renewing tumor cells is responsible for tumorigenesis. This contrasts with the stochastic model of tumor development, which advances that all tumor cells are capable of tumor formation. Within the field of melanoma, the identity and existence of cancer stem cells has been the subject of recent debate. Much of the controversy may be traced to differences in interpretations and definitions related to the cancer stem cell theory, and the use of dissimilar methodologies to study melanoma cells. Accumulating evidence suggests that cancer stem cells may exist in melanoma, although their frequency may vary and they may be capable of phenotypic plasticity. Importantly, these primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but also may confer virulence via immune evasion and multidrug resistance, and potentially via vasculogenic mimicry and transition to migratory and metastasizing derivatives. Therapeutic targeting of melanoma stem cells and the pathways that endow them with virulence hold promise for the design of more effective strategies for amelioration and eradication of this most lethal form of skin cancer.

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“…A specific example of melanoma cell plasticity is vasculogenic mimicry, which characterizes the unique ability of aggressive melanoma cells (but not poorly aggressive melanoma cells) to express endothelia-associated genes and form extracellular matrix (ECM)-rich vasculogenic-like networks in three-dimensional (3-D) culture [14; for review, see 12]. The formation of these networks recapitulates the embryonic development of vasculogenic networks, and they are associated with the distinctly patterned, ECMrich networks observed in aggressive tumors of patients with melanoma [8,[14][15][16][17]. Additional studies have confirmed vasculogenic mimicry in various tumor types [for review, see 12], including the demonstration of blood flow and fluid exchange between tumor cell-lined vascular spaces and endothelium-lined vasculature [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

Seftor¹,

Meltzer²,

Kirschmann³

et al. 2006

J Cellular Molecular Medi

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Cancer pathogenesis involves dynamic interactions within the tumor-host microenvironment. Most noteworthy is cutaneous melanoma which is considered one of the few remaining cancers escalating in incidence [1,2], and thus represents a growing public health burden worldwide [3; for review, see 4; 5]. In addition, uveal melanoma is considered the most common primary intraocular cancer in adults [6], where metastasis occurs in an unpredictable manner in approximately 50% of patients with a primary tumor originating in the choroid or ciliary body of the eye [6]. Without question, the clinical manage- AbstractA dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix -called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability -indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.

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PAS‐positive loops and networks as a prognostic indicator in cutaneous malignant melanoma

Cited by 60 publications

References 17 publications

Tumor Cell Plasticity in Uveal Melanoma

Tumor Cell Plasticity in Uveal Melanoma

Melanoma stem cells: not rare, but well done

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

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