ABC Transporters, Aldehyde Dehydrogenase, and Adult Stem Cells

Guppy, Naomi; Nicholson, Linda J.; Alison, Malcolm R.

doi:10.1007/978-1-61779-002-7_8

Cited by 3 publications

(3 citation statements)

References 98 publications

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“…Interestingly, two of these genes ( ABCG2 and ABCG4 ) co-express together with 16 other members of the ABC transporter family and with 8 aldehyde dehydrogenases (ALDHs) in about 10% of all cells of the BRAF / NRAS wild type cells (Figure 4B , additional Spot E; Table 1 ; Supplementary Table S2 ). The co-expression of ABC-transporters with ALDHs supports their possible role in resistance against chemotherapy and tumor stem cell activity [ 23 – 25 ]. Mapping of this signature into the melanoma data set of Raskin and co-workers shows activation in early stages of melanoma progression ( Supplementary Figure S9B ) [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of ABC transporters is found in cancer stem cells of different tumors and, similarly, ALDH genes have been described as a characteristic feature of cancer stem cells [ 47 ]. Thus, the ABC/ALDH subgroup presents interesting gene candidates for MMICs in our study [ 23 – 25 ]. In addition, our analyses of epigenetic marks of gene expression further favor the presence of a small subpopulation of cells with stemness character.…”

Section: Discussionmentioning

confidence: 99%

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Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

et al. 2016

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Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

et al. 2016

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“…Quiescent tumor cells, as any other quiescent tissue stem cells, do not proliferate nor do they express estrogen receptors [37]. However, they express proteins that are associated with the resistance to chemical toxicity such as ALDH, or ABC family transporters (which are often used as stemness markers) [54]. These properties make them quite resistant to any conventional chemo or hormonal therapy.…”

Section: The Quiescent Tumor Cells and Vegf Enrichment Of ε-Pcl Implantmentioning

confidence: 99%

Eta polycaprolactone (ε-PCL) implants appear to cause a partial differentiation of breast cancer lung metastasis in a murine model

et al. 2023

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Background Cells in every epithelium can be roughly divided in three compartments: stem cell (SC) compartment, transient amplifying cell (TA) compartment and terminally differentiated (TD) compartment. Maturation of stem cells is characterized by epithelial stromal interaction and sequential maturational movement of stem cell’s progeny through those compartments. In this work we hypothesize that providing an artificial stroma, which murine breast cancer metastatic cells can infiltrate, will induce their differentiation. Methods BALB/c female mice were injected with 106 isogenic 4T1 breast cancer cells labeled with GFP. After 20 days primary tumors were removed, and artificial ε-PCL implants were implanted on the contralateral side. After 10 more days mice were sacrificed and implants along with lung tissue were harvested. Mice were divided in four groups: tumor removal with sham implantation surgery (n = 5), tumor removal with ε-PCL implant (n = 5), tumor removal with VEGF enriched ε-PCL implant (n = 7) and mice without tumor with VEGF enriched ε-PCL implant (n = 3). Differentiational status of GFP + cells was assessed by Ki67 and activated caspase 3 expression, thus dividing the population in SC like cells (Ki67+/dim aCasp3−), TA like cells (Ki67+/dim aCasp3+/dim) and TD like cells (Ki67− aCasp3+/dim) on flow cytometry. Results Lung metastatic load was reduced by 33% in mice with simple ε-PCL implant when compared to tumor bearing group with no implant. Mice with VEGF enriched implants had 108% increase in lung metastatic load in comparison to tumor bearing mice with no implants. Likewise, amount of GFP + cells was higher in simple ε-PCL implant in comparison to VEGF enriched implants. Differentiation-wise, process of metastasizing to lungs reduces the average fraction of SC like cells when compared to primary tumor. This effect is made more uniform by both kinds of ε-PCL implants. The opposite process is mirrored in TA like cells compartment when it comes to averages. Effects of both types of implants on TD like cells were negligible. Furthermore, if gene expression signatures that mimic tissue compartments are analyzed in human breast cancer metastases, it turns out that TA signature is associated with increased survival probability. Conclusion ε-PCL implants without VEGF can reduce metastatic loads in lungs, after primary tumor removal. Both types of implants cause lung metastasis differentiation by shifting cancer cells from SC to TA compartment, leaving the TD compartment unaffected.

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Mesenchymal Stem/Stromal Cells Derived From a Reproductive Tissue Niche Under Oxidative Stress Have High Aldehyde Dehydrogenase Activity

Kusuma

Abumaree

Pertile

et al. 2016

Stem Cell Rev and Rep

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The use of mesenchymal stem/stromal cells (MSC) in regenerative medicine often requires MSC to function in environments of high oxidative stress. Human pregnancy is a condition where the mother's tissues, and in particular her circulatory system, are exposed to increased levels of oxidative stress. MSC in the maternal decidua basalis (DMSC) are in a vascular niche, and thus would be exposed to oxidative stress products in the maternal circulation. Aldehyde dehydrogenases (ALDH) are a large family of enzymes which detoxify aldehydes and thereby protect stem cells against oxidative damage. A subpopulation of MSC express high levels of ALDH (ALDH(br)) and these are more potent in repairing and regenerating tissues. DMSC was compared with chorionic villous MSC (CMSC) derived from the human placenta. CMSC reside in vascular niche and are exposed to the fetal circulation, which is in lower oxidative state. We screened an ALDH isozyme cDNA array and determined that relative to CMSC, DMSC expressed high levels of ALDH1 family members, predominantly ALDH1A1. Immunocytochemistry gave qualitative confirmation at the protein level. Immunofluorescence detected ALDH1 immunoreactivity in the DMSC and CMSC vascular niche. The percentage of ALDH(br) cells was calculated by Aldefluor assay and DMSC showed a significantly higher percentage of ALDH(br) cells than CMSC. Finally, flow sorted ALDH(br) cells were functionally potent in colony forming unit assays. DMSC, which are derived from pregnancy tissues that are naturally exposed to high levels of oxidative stress, may be better candidates for regenerative therapies where MSC must function in high oxidative stress environments.

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ABC Transporters, Aldehyde Dehydrogenase, and Adult Stem Cells

Cited by 3 publications

References 98 publications

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

Eta polycaprolactone (ε-PCL) implants appear to cause a partial differentiation of breast cancer lung metastasis in a murine model

Mesenchymal Stem/Stromal Cells Derived From a Reproductive Tissue Niche Under Oxidative Stress Have High Aldehyde Dehydrogenase Activity

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