Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer
<p>Long-term label-retaining cells (LT+) are present in cell lines and cultures from patient cells and display cancer stem cell characteristics. (<b>A</b>) MDA-MB-231 cells were stained with DDAO and cultivated 8DIV (days in vitro) in monolayers or as mammospheres (CM-sph). (<b>B</b>) Also, the MCF7 cell line showed an LT+ population, which was higher in mammosphere assays (cytometry assay) than in monolayers. (<b>C</b>) Growing patterns of LT+ and LT− cells from patient Pa00 cells stained and grown 8DIV (400 cells/well) and then sorted according to their DDAO content. The number of living cells after 3DIV was checked by methyl purple assay. LT− cells grew similar to controls and faster than LT+ cells. The growth of the control cells has been represented with a blue horizontal line. (<b>D</b>) Docetaxel dose–response curves for LT+, LT−, and control cells. Pa00 cells were stained with DDAO and grown for 8DIV, sorted by their content of DDAO, and grown with increasing concentrations of docetaxel. LT+ cells showed greater resistance against docetaxel than LT−, and respective IC50 are marked by perpendicular lines. (<b>E</b>) 5000 Pa00 cells were injected in nude mice in each case. The tumor volumes are similar when injecting LT− and control non-separated cells but smaller when injecting LT+ cells. All tumors were palpable at the same time. LT+ tumors grew slowly compared to those in the control or LT− group. (<b>F</b>) Table of number of injected mice and tumor formation of the different cell types (<span class="html-italic">n</span> = 3 all experiment; * <span class="html-italic">p</span> < 0.05).</p> "> Figure 2
<p>Pigmented Epithelium-Derived Factor (PEDF) increases the number of LT+ cells and the docetaxel resistance of breast cancer cells. (<b>A</b>) Cells treated with chronic PEDF showed a different morphology than control cells. (<b>B</b>) Quantification of morphological differences induced by PEDF treatment. Cells in the micrographs were measured via ImageJ program using the mask shown in Figure (<b>A</b>). (<b>C</b>) Growing pattern after 3DIV of PEDF treated cells and control. PEDF chronically treated cells grew slower than control. (<b>D</b>) Docetaxel dose–response curve of PEDF chronically treated cells and control. PEDF chronically treated cells were more resistant against docetaxel. (<b>E</b>) Histology of PEDF treated tumors and control tumors. Optical microscopic observation shows visible changes in cells chronically treated with PEDF, with a qualitative increase in both cytoplasmic density and the external matrix. Necrotic areas are bigger in controls compared to those with PEDF treatment. Black arrows show mask examples of areas compatible with acellular necrotic spaces. (<b>F</b>) Docetaxel dose–response curve of LT+ PEDF treated cells and LT+ untreated cells, <span class="html-italic">n</span> = 3. LT+ PEDF chronically treated cells were more resistant to docetaxel than untreated ones. (<b>G</b>) PEDF-treated cells grew more slowly than control cells, meaning that the dye-retaining population is up to three times larger than with PEDF treatment. (<b>H</b>) BCRP1 marker immunohistochemistry in control cells. (<b>I</b>) BCRP1 marker immunohistochemistry in PEDF-treated cells. (<b>J</b>) CD133 marker immunohistochemistry in control cells (<b>K</b>) CD133 marker immunohistochemistry in PEDF-treated cells. White arrows in (<b>H</b>–<b>K</b>) shown examples of the abundance of cells in different mitotic phases. (<b>L</b>–<b>O</b>) Insert at high magnification of the yellow square in (<b>H</b>–<b>K</b>). <span class="html-italic">n</span> = 3 in all experiments; * <span class="html-italic">p</span> < 0.05. Bar in (<b>H</b>–<b>K</b>) is 50 µm. Bar in (<b>L</b>–<b>O</b>) is 10 µm.</p> "> Figure 3
<p>CTE-PEDF induces loss of anchorage and cell death in vivo and reduces resistance against docetaxel. (<b>A</b>) CTE-PEDF construction from 195 to 418 aa of PEDF and with glutamic acid instead of serine in position 227. (<b>B</b>) Pa00 cells were treated chronically with CTE (200 ng/µL). After a week, they showed an increase in anoikis figures. (<b>C</b>) Quantification of CTE-PEDF induced morphological changes in nuclear and cytoplasmic areas and cell distance. (<b>D</b>) Growing pattern after 3DIV of CTE-PEDF treated cells and control. Treated cells survive for less time than control cells. (<b>E</b>) Docetaxel dose–response curve of CTE-treated cells and control. CTE chronically treated cells were less resistant to docetaxel (<span class="html-italic">n</span> = 3 in all experiments; * <span class="html-italic">p</span> < 0.05, *** <span class="html-italic">p</span> < 0.001). Bar 50 µm.</p> "> Figure 4
<p>Cter-PEDF and CTE-PEDF treatments decrease in vivo cancer stem cell markers. (<b>A</b>) Cytometry assay showing the smaller number of CSC in treated cells compared to control. (<b>B</b>) Quantification of positive cells in acute treatment compared to control. (<b>C</b>) Quantification of positive cells in chronic treatment compared to control (<span class="html-italic">n</span> = 3 in all experiments; *** <span class="html-italic">p</span> < 0.001).</p> "> Figure 5
<p>PEDF and CTE-PEDF treatments modified in vivo cancer stem cell markers. (<b>A</b>) Examples of xenografts of the PEDF-, CTE-, and control-injected cells. (<b>B</b>) Immunofluorescence of cells positive (arrows) for CD133 and BCRP1, respectively, in xenografts of chronic treatments. Immunocytochemistry with hematoxylin is shown at 20×. Immunocytochemistry assays with CD133 and BCRP1 are shown at 40× with DAPI nuclear staining. (<b>C</b>) Differential effects on cell viability of PEDF and CtE-PEDF treatments over Pa00 tumoral cells in culture. a: Statistically significant differences between Cter and control or PEDF-treated cells, <span class="html-italic">p</span> < 0.05. b: Statistically significant differences between PEDF and control or Cter-treated cells, <span class="html-italic">p</span> < 0.05.</p> "> Figure 6
<p>LT+ and BCRP1+ cells used in xenograft assays showing the effect of CTE-PEDF treatments in vivo and the synergy of this effect with chemo and radiotherapy. (<b>A</b>) Cell cytometry of PEDF-treated and untreated cells. LT+ cells are more abundant after PEDF treatment. (<b>B</b>) Quantification of three independent flow cytometry experiments in A. (<b>C</b>) Xenografts resulting from cells positive for stem cell markers and slow-cycling LT+ cells are more resistant tumors when subjected to dose–response assays after dissection and placed in cell culture. (<b>D</b>) Cells expressing the cancer stem cell marker BCRP1 were injected at different cell concentrations. Control-negative cells were also injected. In all cases, an assay was performed with and without treatment with the carboxyl end of PEDF (Cter-PEDF). The xenograft tumors of the Cter-treated cells appear time-delayed (in green) with respect to their controls (in red). (<b>E</b>) Consecutive treatment with radiotherapy (8 treatments and 22 treatments at 6 Gy) downregulates stem cell cancer markers such as the p21 mRNA involved in cell cycle arrest of these cells. (<b>F</b>) The effect of CTE is also synergistic with radiotherapeutic treatments, as it decreases cancer stem cell viability significantly more with CTE treatment and radiotherapy (gray bars) than with radiotherapy alone or with a negative control peptide (CTA peptide without negative charge, white bars). a: statistically significant differences (<span class="html-italic">p</span> < 0.05; compared to the non-irradiated control. b: statistically significant differences compared to 6 Gy treatment without CTE. (<span class="html-italic">p</span> < 0.05; *; <span class="html-italic">p</span> < 0.01; ***).</p> "> Figure 7
<p>Hypothesis of the exhaustion and depletion of tumor stem cells by blocking the PEDF self-renewal factor signaling pathway. This could result in increased proliferation of chemotherapy-responsive cells and decreased tumor resistance and relapse frequency.</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Long-Term Label-Retaining Cells Exhibit Characteristics of Cancer Stem Cells in Cancer Cell Lines and in Patient Cells
2.2. PEDF Modulate CSC Properties, Producing an Increase in Drug Resistance and Proportion of LT+ Cells
2.3. Cter-PEDF Counteracts the Effects of Native PEDF, Decreasing the Resistance in Tumors and Inducing Anoikis and Depleting CSC
2.4. CTE-PEDF and Cter-PEDF Depletes Percentage of CSC Expressing Markers
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Staining with DDAO and Sorting
4.3. Cytometry Assay
4.4. Gene Expression
4.5. Xenografts
4.6. PEDF and Cter-PEDF, CTE-PEDF Production
4.7. Treatment with PEDF and CTE-PEDF
4.8. Treatment with Radiotherapy and CTE-PEDF
4.9. Dose–Response Curve
4.10. MTT Assay
4.11. Methyl Purple Assay
4.12. Histology
4.13. Analysis of Cell Morphology
4.14. Immnuno Assays
4.15. Measurements of the Xenograft Tumors
4.16. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AC133 | Glycosylated epitope of the pentaspan membrane protein CD133, originally identified as a marker for CD34 + hematopoietic stem and progenitor cells. |
BCRP1 | Breast cancer resistance protein (BCRP1), also known as placenta-specific ATP-binding cassette (ABC) protein (ABCP) or ABC G-subfamily member 2 (ABCG2). |
CD133 | CD133 antigen, also known as prominin-1, is a glycoprotein that in humans is encoded by the PROM1 gene. It has been proposed to act as an organizer of cell membrane topology. |
CM-sph | Mammospheres. |
CSC | Cancer stem cells. |
CTA-PEDF | Carboxy-terminal fragment of PEDF (Ala227). |
CTE-PEDF | Carboxy-terminal fragment of PEDF (Glu227). |
DDAO | Near-infrared (NIR) red fluorescent probe with excitation wavelength (600–650 nm) and long emission wavelength (λem = 656 nm). DIV: days in vitro. |
ECM | Extracellular matrix. |
EpCAM | Epithelial cell adhesion molecule, also known as CD326. |
GADPH | Glyceraldehyde 3-phosphate dehydrogenase. |
LT+ | Long-term label-retaining cells. |
MDA-MB-231 | Triple-Negative Breast Cancer Cell Line. |
MCF7 | Epithelial cell line from breast tissue of a patient with metastatic adenocarcinoma. |
p21 | p21 Cip1 (alternatively p21 Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1. |
PEDF | Pigment Epithelium-Derived Factor. |
PEDFr | PEDF receptor. |
PKA | Protein kinase A (EC 2.7.11.11). |
Tert | Telomerase protein. |
TIC | Tumor-initiating cells. |
EMT | Epithelial–mesenchymal transition. |
TROP2 | Transmembrane glycoprotein encoded by Tacstd2 gene overexpressed in cancers. |
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Gil-Gas, C.; Sánchez-Díez, M.; Honrubia-Gómez, P.; Sánchez-Sánchez, J.L.; Alvarez-Simón, C.B.; Sabater, S.; Sánchez-Sánchez, F.; Ramírez-Castillejo, C. Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer. Cancers 2023, 15, 5422. https://doi.org/10.3390/cancers15225422
Gil-Gas C, Sánchez-Díez M, Honrubia-Gómez P, Sánchez-Sánchez JL, Alvarez-Simón CB, Sabater S, Sánchez-Sánchez F, Ramírez-Castillejo C. Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer. Cancers. 2023; 15(22):5422. https://doi.org/10.3390/cancers15225422
Chicago/Turabian StyleGil-Gas, Carmen, Marta Sánchez-Díez, Paloma Honrubia-Gómez, Jose Luis Sánchez-Sánchez, Carmen B. Alvarez-Simón, Sebastia Sabater, Francisco Sánchez-Sánchez, and Carmen Ramírez-Castillejo. 2023. "Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer" Cancers 15, no. 22: 5422. https://doi.org/10.3390/cancers15225422