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Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment.

Gray ES, Reid AL, Bowyer S, Calapre L, Siew K, Pearce R, Cowell L, Frank MH, Millward M, Ziman M - J. Invest. Dermatol. (2015)

Bottom Line: Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation.Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01).Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01).

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, Edith Cowan University, Perth, Washington, Australia.

ABSTRACT
Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP-binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-κβ (RANK) in individual circulating tumor cells (CTCs) from 40 late-stage (III-IV) and 16 early-stage (I-II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy.

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Receptor activator of NF-κβ (RANK) and ATP-binding cassette sub-family B member 5 (ABCB5) expression in metastases from patients with circulating tumor cells (CTCs) expressing these markers. Immunofluorescence staining of metastatic melanoma tissue corresponding to patients MM15 (a) and MM26 (b). MART-1 staining was used to identify melanoma cells. Original magnification × 400. Scale bar=20 μm.
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fig3: Receptor activator of NF-κβ (RANK) and ATP-binding cassette sub-family B member 5 (ABCB5) expression in metastases from patients with circulating tumor cells (CTCs) expressing these markers. Immunofluorescence staining of metastatic melanoma tissue corresponding to patients MM15 (a) and MM26 (b). MART-1 staining was used to identify melanoma cells. Original magnification × 400. Scale bar=20 μm.

Mentions: Next we analyzed the expression of RANK and ABCB5 in metastatic tissue from two patients in which CTCs expressing these two markers could be detected: patient MM15, in which 100% of detected CTCs were RANK+ and 25% were ABCB5+, and patient MM26, in which 75% of CTCs were RANK+ but no ABCB5+ CTCs were detected. The metastases analyzed were removed from these patients within 1 month prior to blood collection for CTC analysis. Immunofluorescence staining of the tissue was performed using antibodies to MART-1 to define the tumor cells together with either RANK or ABCB5 (Figure 3). In contrast with the large percentage found among CTCs, the number of RANK (~2%) and ABCB5 (6–7.5%)-expressing cells was sparse within the tumor.


Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment.

Gray ES, Reid AL, Bowyer S, Calapre L, Siew K, Pearce R, Cowell L, Frank MH, Millward M, Ziman M - J. Invest. Dermatol. (2015)

Receptor activator of NF-κβ (RANK) and ATP-binding cassette sub-family B member 5 (ABCB5) expression in metastases from patients with circulating tumor cells (CTCs) expressing these markers. Immunofluorescence staining of metastatic melanoma tissue corresponding to patients MM15 (a) and MM26 (b). MART-1 staining was used to identify melanoma cells. Original magnification × 400. Scale bar=20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4504811&req=5

fig3: Receptor activator of NF-κβ (RANK) and ATP-binding cassette sub-family B member 5 (ABCB5) expression in metastases from patients with circulating tumor cells (CTCs) expressing these markers. Immunofluorescence staining of metastatic melanoma tissue corresponding to patients MM15 (a) and MM26 (b). MART-1 staining was used to identify melanoma cells. Original magnification × 400. Scale bar=20 μm.
Mentions: Next we analyzed the expression of RANK and ABCB5 in metastatic tissue from two patients in which CTCs expressing these two markers could be detected: patient MM15, in which 100% of detected CTCs were RANK+ and 25% were ABCB5+, and patient MM26, in which 75% of CTCs were RANK+ but no ABCB5+ CTCs were detected. The metastases analyzed were removed from these patients within 1 month prior to blood collection for CTC analysis. Immunofluorescence staining of the tissue was performed using antibodies to MART-1 to define the tumor cells together with either RANK or ABCB5 (Figure 3). In contrast with the large percentage found among CTCs, the number of RANK (~2%) and ABCB5 (6–7.5%)-expressing cells was sparse within the tumor.

Bottom Line: Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation.Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01).Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01).

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, Edith Cowan University, Perth, Washington, Australia.

ABSTRACT
Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP-binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-κβ (RANK) in individual circulating tumor cells (CTCs) from 40 late-stage (III-IV) and 16 early-stage (I-II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy.

Show MeSH
Related in: MedlinePlus