Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

Ma, Jie; Frank, Markus H.

doi:10.2174/187152010790909254

Cited by 16 publications

(14 citation statements)

References 45 publications

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“…In several malignancies, a subpopulation of cells known as cancer stem cells (CSC) is linked to recurrence and disease progression [8, 9]. The presence of CSC limits the therapeutic effect of treatments, since they appear to be refractory to treatment.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of CSC limits the therapeutic effect of treatments, since they appear to be refractory to treatment. These CSC have the potential of extensive proliferation, differentiation and maintenance of tumor growth, despite the fact that they comprise only a small fraction of neoplastic cells [8, 10–12]. As a result, failure of targeted elimination of these so-called quiescent CSC leads to recurrence of the disease [13].…”

Section: Introductionmentioning

confidence: 99%

“…Of particular interest is the stem cell marker ABCB5, an ATP-binding cassette (ABC) multidrug resistance transporter, which also mediates cell fusion, stem cell function, and vasculogenic plasticity [14]. Cutaneous melanoma is enriched for a subpopulation of cells positive for ABCB5, and ABCB5 has been identified as a molecular marker for melanoma progression, with a distinct subpopulation of ABCB5+ cells displaying increased tumorigenicity [8, 10–13, 15]. Moreover, ABCB5+ cells have been shown to play an active role in conferring chemoresistance through the efflux function of ABCB5 [16, 17].…”

Section: Introductionmentioning

confidence: 99%

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Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma

et al. 2015

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Conjunctival melanoma (CM) is a rare ocular malignancy with a high tendency to reoccur locally and with a high risk of metastatic disease. Metastases are often unresponsive to conventional treatment. Recently, an animal model was set up using human CM cells. Orthotopic xenografts from human CM were created by subconjunctival injection of three different CM cell lines into NOD.Cg-Prkdc^scid IL2rg^tm1Wjl/SzJ (NSG) mice. Subconjunctival injection of cultured CM cells led to excellent subconjunctival growth, but no metastases were found. When single-cell suspensions were obtained from the subconjunctival xenografts and passaged in vivo, all mice developed metastases. As recent findings indicate that cancer stem cells are linked to tumor recurrences, we used this new murine model to determine the expression of the stem cell marker ABCB5 during tumor progression. Expression of the ABCB5 protein was determined in three cell lines and during different stages of tumor development as observed in our model. All three cell lines contained a subpopulation of cells positive for ABCB5. During tumor development, expression of ABCB5 increased during phases of tumor expansion. Furthermore, expression of ABCB5 was increased in metastases. Using this model for CM, we were able to initiate metastatic spread and determine the expression of the stem cell marker ABCB5 during different stages of tumor development, identifying ABCB5 as a potential novel therapeutic target. This study illustrates the potential of our newly established murine model.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma

et al. 2015

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“…However, schedules and doses of Mek inhibitors compatible with satisfactory antitumor efficacy associated with low systemic toxicity need to be further defined [15-19]. On the other hand, it would be relevant to determine whether the pathway signature of the bulk tumor characterizes also the melanoma initiating cell (MIC) compartment in order to favor potentially more curative MIC-effective molecularly targeted approaches [20-22]. In fact, increasing experimental evidence supports the assertion that many tumors including melanomas, contain Cancer Stem Cells (CSC) or Tumor-Initiating Cells (TIC) and that they affect tumor biology, thus acquiring dramatic clinical relevance [4,20,23].…”

Section: Introductionmentioning

confidence: 99%

Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts

Sette¹,

Fecchi

Salvati

et al. 2013

J Exp Clin Cancer Res

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One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets.

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“…Although melanoma can be cured by surgical resection before the cancer has spread, metastatic melanoma is one of the most aggressive and drug-resistant cancers with very poor overall survival [1; 2; 3]. A more detailed understanding of the cellular mechanisms that drive metastatic melanoma progression would improve the development and assessment of more effective new or emerging treatment modalities that target disseminated disease.…”

Section: Introductionmentioning

confidence: 99%

Isolation of tumorigenic circulating melanoma cells

Lin

Alloo

et al. 2010

Biochemical and Biophysical Research Communications

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Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-tomouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγ null recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities.

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Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

Cited by 16 publications

References 45 publications

Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma

Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma

Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts

Isolation of tumorigenic circulating melanoma cells

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