Identification of Cancer Stem Cell Subpopulations in Head and Neck Metastatic Malignant Melanoma

Yoganandarajah, Vithushiya; Patel, Josie; Schaijik, Bede van; Bockett, Nicholas; Brasch, Helen D.; Paterson, Erin; Sim, Dalice; Davis, Paul F.; Roth, Imogen; Itinteang, Tinte; Tan, Swee T.

doi:10.3390/cells9020324

Cited by 21 publications

(30 citation statements)

References 55 publications

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“…Three out of four primary cell lines derived from four different HNmMM tissue samples formed tumorspheres in vitro. As with the current study of mHNcSCC, the formation of tumorspheres in HNmMM-derived primary cell lines in vitro, provides preliminary functional evidence of the presence of CSCs in HNmMM tissues (44).…”

Section: Discussionsupporting

confidence: 53%

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma

et al. 2020

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Cancer stem cells (CSCs) have been identified in many cancer types including primary head and neck cutaneous squamous cell carcinoma (HNcSCC). This study aimed to identify and characterize CSCs in metastatic HNcSCC (mHNcSCC). Immunohistochemical staining performed on mHNcSCC samples from 15 patients demonstrated expression of the induced pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4, and c-MYC in all 15 samples. In situ hybridization and RT-qPCR performed on four of these mHNcSCC tissue samples confirmed transcript expression of all five iPSC markers. Immunofluorescence staining performed on three of these mHNcSCC samples demonstrated expression of c-MYC on cells within the tumor nests (TNs) and the peri-tumoral stroma (PTS) that also expressed KLF4. OCT4 was expressed on the SOX2+/NANOG+/KLF4+ cells within the TNs, and the SOX2+/NANOG+/KLF4+ cells within the PTS. RT-qPCR demonstrated transcript expression of all five iPSC markers in all three mHNcSCC-derived primary cell lines, except for SOX2 in one cell line. Western blotting showed the presence of SOX2, KLF4, and c-MYC but not OCT4 and NANOG in the three mHNcSCC-derived primary cell lines. All three cell lines formed tumorspheres, at the first passage. We demonstrated an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ CSC subpopulation and an OCT4+/NANOG-/SOX2+/KLF4+/c-MYC+ subpopulation within the TNs, and an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ subpopulation within the PTS of mHNcSCC.

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Section: Discussionsupporting

confidence: 53%

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma

et al. 2020

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“…CSCs have been identified in many cancer types, including OCSCC of different subsites, 9 – 11 glioblastoma, 12 renal clear cell carcinoma, 13 primary 14 and metastatic 15 colon adenocarcinoma, and metastatic malignant melanoma. 16 , 17 We have recently reported the presence of 4 CSC subpopulations within human MDHNcSCC: an OCT4 + /NANOG + /SOX2 + /KLF4 + /c-MYC + subpopulation within the TNs, the PTS, the endothelium of the microvessels within the PTS, and an OCT4 + /NANOG − /SOX2 + /KLF4 + /c-MYC + subpopulation solely within the PTS. 27 These CSCs have been suggested as a novel therapeutic target 5 by modulating the RAS.…”

Section: Discussionmentioning

confidence: 96%

“…CSCs have been identified in many cancer types, including oral cavity SCC (OCSCC) of different subsites, 9 – 11 glioblastoma, 12 renal clear cell carcinoma, 13 primary 14 and metastatic 15 colon adenocarcinoma, and metastatic malignant melanoma. 16 , 17 …”

Section: Introductionmentioning

confidence: 99%

Cancer Stem Cells in Head and Neck Cutaneous Squamous Cell Carcinoma Express Cathepsins

Featherston

Brasch

Siljee

et al. 2020

Plastic and Reconstructive Surgery - Global Open

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Background: Cancer stem cell (CSC) subpopulations within moderately differentiated head and neck cutaneous squamous cell carcinoma (MDHNcSCC) express the components of the renin–angiotensin system (RAS). This study investigated the expression of cathepsins B, D, and G, which constitute bypass loops of the RAS, by CSCs in MDHNcSCC. Methods: Immunohistochemical staining was performed on MDHNcSCC tissue samples from 15 patients to determine the expression of cathepsins B, D, and G. Co-localization of these cathepsins with the embryonic stem cell markers Octamer-binding transcription factor 4 (OCT4) and c-MYC was investigated with immunofluorescence staining. Reverse transcription quantitative polymerase chain reaction was performed on 5 MDHNcSCC tissue samples to investigate transcript expression of cathepsins B, D and G. Western blotting and enzymatic activity assays were performed on 5 MDHNcSCC tissue samples and 6 MDHNcSCC-derived primary cell lines to confirm protein expression, transcript expression, and functional activity of these cathepsins, respectively. Results: Immunohistochemical staining demonstrated the expression of cathepsins B, D, and G in all MDHNcSCC tissue samples. Immunofluorescence staining showed localization of cathepsins B and D to the c-MYC+ CSC subpopulations and the OCT4+ CSC subpopulations within the tumor nests and the peritumoral stroma. Cathepsin G was expressed on the tryptase+/c-MYC+ cells within the peritumoral stroma. Reverse transcription quantitative polymerase chain reaction demonstrated transcript expression of cathepsins B, D and G in the MDHNcSCC tissue samples. Western blotting and enzymatic activity assays confirmed protein expression and functional activity of cathepsins B and D in the MDHNcSCC tissue samples and MDHNcSCC-derived primary cell lines, respectively. Conclusions: Cathepsins B, D, and G are expressed in MDHNcSCC with functionally active cathepsins B and D localizing to the CSC subpopulations, and cathepsin G is expressed by mast cells, suggesting the potential use of cathepsin inhibitors in addition to RAS blockade to target CSCs in MDHNcSCC.

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“…Although our approach is theoretical, there is recent evidence of an invariant stem cell hierarchy in glioblastoma tumors giving rise to progenitor cells with an extensive self-maintenance capacity [22,31]. There is also evidence of subpopulations of cells showing a differential expression of embryonic stem cell markers in head and neck squamous cell carcinoma, colon adenocarcinoma, melanoma, and buccal squamous cell carcinoma [23,[33][34][35], in addition to evidence that more differentiated cells can generate tumors [9,10,17,25,28]. Moreover, recent findings on antibody-drug conjugates (ADC) showed that the targeting of Lgr5(+) colon CSCs with an ADC controlled the disease, but did not eliminate it, as observed in their reported growth curves [52].…”

Section: Discussionmentioning

confidence: 99%

“…This idea has been put forward elsewhere [16]. Although recent reports [31][32][33][34][35] mention the existence of different populations of cancer cells differentially expressing embryonal stem cell markers at the mRNA and protein level, confirmation of their stemness potential and whether they belong to the same hierarchical structure were not tested. In addition to this complexity, Liu et al postulated that CSCs can shift between two different stem-like states [36].…”

Section: Hypothesismentioning

confidence: 99%

A Mathematical Model of Average Dynamics in a Stem Cell Hierarchy Suggests the Combinatorial Targeting of Cancer Stem Cells and Progenitor Cells as a Potential Strategy against Tumor Growth

Molina-Peña

Tudón-Martínez

Aquines-Gutiérrez

2020

Cancers

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The cancer stem cell hypothesis states that tumors are maintained by a small subpopulation of stem-like cells, often called cancer stem cells (CSCs) or tumor initiating cells. CSCs can self-renew and give rise to more differentiated cells, which comprise the bulk of the tumor. In addition, CSCs are resistant to conventional therapy, which suggests that they are responsible for tumor relapse. This has led researchers to increase efforts to develop directed therapies against CSCs. However, some experiments in mice have shown that the elimination of CSCs might not ensure tumor eradication. This may be due to different events, such as residual CSCs after treatment, the plasticity of cells within the tumor, the presence of different CSCs having their own hierarchy within the same tumor, and the ability of more differentiated cells to maintain the disease, among others. Trying to decipher this complexity may benefit from dissecting the whole in its parts. Here, we hypothesize that tumor relapse after the selective targeting of CSCs may be due to intermediate progenitor (P) cells that can maintain the tumor volume. In order to support the hypothesis, we implemented a mathematical model derived using pseudo-reactions representing the events of each cell subpopulation within the tumor. We aimed to test if a minimal unidirectional hierarchical model consisting of CSCs, P, and terminally differentiated (D) cells could be adjusted to experimental data for selective CSC targeting. We further evaluated therapies ranging from nonselective to specifically directed and combination therapy. We found that selective killing of the CSC compartment has a delaying effect on the overall exponential tumor growth, but was not able to eliminate the disease. We show that therapy that targets both CSCs and intermediate progenitor (P) cells with a sufficient capacity to proliferate and differentiate could represent a more efficient treatment option for tumor depletion. Testing this hypothesis in vivo may allow us to discriminate within the array of possibilities of tumor relapse, and further open the idea of combination therapy against different subpopulations of tumor cells instead of segregating CSCs and bulk tumor cells.

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Identification of Cancer Stem Cell Subpopulations in Head and Neck Metastatic Malignant Melanoma

Cited by 21 publications

References 55 publications

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma

Cancer Stem Cells in Head and Neck Cutaneous Squamous Cell Carcinoma Express Cathepsins

A Mathematical Model of Average Dynamics in a Stem Cell Hierarchy Suggests the Combinatorial Targeting of Cancer Stem Cells and Progenitor Cells as a Potential Strategy against Tumor Growth

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