Cancer Conditioned Medium Modulates Functional and Phenotypic Properties of Human Decidua Parietalis Mesenchymal Stem/Stromal Cells

E Bahattab; T Khatlani; F M Abomaray; S A Messaoudi; M H Abumaree

doi:10.1007/s13770-019-00207-w

. 2019 Nov 1;16(6):615–630. doi: 10.1007/s13770-019-00207-w

Cancer Conditioned Medium Modulates Functional and Phenotypic Properties of Human Decidua Parietalis Mesenchymal Stem/Stromal Cells

E Bahattab ¹, T Khatlani ², F M Abomaray ^3,^✉, S A Messaoudi ⁴, M H Abumaree ^2,^5,^✉

PMCID: PMC6879693 PMID: 31824824

Abstract

Background:

Mesenchymal Stem/Stromal Cells (MSCs) from the decidua parietalis (DPMSCs) of human term placenta express several molecules with important biological and immunological properties. DPMSCs induce natural killer cell expression of inflammatory receptors and their cytotoxic activity against cancer cells. These properties make DPMSCs promising therapeutical agent for cancer. The successful development of MSCs as an anti-cancer therapeutic cells rely on their ability to function in a hostile inflammatory and oxidative stress cancer environment. Here, we studied the effects of conditioned medium obtained from the culture of breast cancer cells (CMMDA-231) on the functional and phenotypic properties of DPMSCs.

Methods:

DPMSCs were cultured with CMMDA-231 and important functions of DPMSCs were measured. The effect of CMMDA-231 on DPMSC expression of several genes with different functions was also evaluated.

Results:

DPMSCs were able to function in response to CMMDA-231, but with reduced proliferative and adhesive potentials. Preconditioning of DPMSCs with CMMDA-231 enhanced their adhesion while reducing their invasion. In addition, CMMDA-231 modulated DPMSC expression of many genes with various functional (i.e., proliferation, adhesion, and invasion) properties. DPMSCs also showed increased expression of genes with anti-cancer property.

Conclusion:

These data show the ability of DPMSCs to survive and function in cancer environment. In addition, preconditioning of DPMSCs with CMMDA-231 enhanced their anti-cancer properties and thus demonstrating their potential as an anti-cancer therapeutic agent. However, future studies are essential to reveal the mechanism underlying the effects of MDA-231 on DPMSC functional activities and also to confirm the anti-cancer therapeutic potential of DPMSCs.

Keywords: Proliferation, Adhesion, Migration, Invasion, Gene expression

Introduction

Previously, we have reported the isolation and characterization of mesenchymal stem/stromal cells (MSCs) from the maternal tissue of human term placenta, specifically from a region known as decidua parietalis(DPMSCs) [1]. These MSCs are adult multipotent cells with multipotent differentiation potential into the three mesenchymal lineages of adipocytes, osteocytes, and chondrocytes [1]. DPMSCs express several molecules with important biological and immunological properties including proliferation, adhesion, migration, invasion, angiogenesis, differentiation, immunomodulation and angiogenesis [1].

Recently, we studied the consequences of the interaction between DPMSCs and natural killer cells (NK cells), lymphocytes with specific cytotoxic immune functions against virally infected cells and tumor cells [2]. We reported that DPMSCs induce NK cell expression of inflammatory receptors [i.e., IL18 receptors (IL-18Rα, IL-18Rβ)] and Toll like receptor (TLR-7) [3]. These receptors are known for their anti-cancer functional activities. We also reported the ability of DPMSCs to enhance NK cell anti-cancer activity [3]. These results show the anti-cancer therapeutic potential of DPMSCs.

The use of MSCs as a therapy for cancers relies on the ability of transplanted MSCs to function normally in tumor microenvironment. This microenvironment shares similarity with an inflamed tissue that contains non-cellular and cellular components as well as secreted inflammatory and oxidative molecules [4]. This is why tumors are considered as a wound healing, which is defined as a dynamic process of chronic inflammation that promotes proliferation of cells and remodelling of tissues [5]. Similarly, chronic inflammation is responsible for cancer initiation (tumorigenesis) and progression (tumor metastasis) [5].

Tumor microenvironment contains proinflammatory mediators (i.e., cytokines, chemokines, and growth factors, etc.) secreted by cancer cells, cancer associated fibroblasts, tumor infiltrating immune cells and other cell types [4, 5]. This tumor microenvironment stimulates tumor growth and cancer progression. In addition, it provides a chemotactic stimuli to attract the transplanted MSCs to the tumor site where they must perform their functional activities in a harsh and hostile microenvironment [6–11]. Several studies reported the harmful effect of tumor microenvironment on the function of transplanted MSCs, and therefore limiting their clinical applications [6–12].

Therefore, for successful use of DPMSCs as therapeutic agent in cancer patients, it is necessary to investigate their functional responses to cancer environment. In this study, we examined the effects of cancer environment on the functions of DPMSCs and their expression of various genes with various functional properties. We exposed DPMSCs to CMMDA-231 [conditioned medium (CM) obtained from the culture of MDA-231 (breast cancer cell line)] and their functional and phenotypic properties were evaluated. We found that DPMSCs maintained their functional activities (i.e., proliferation, adhesion, migration and invasion) under a continuous exposure to CMMDA-231, but with reduced proliferation and adhesion while showing enhanced invasion. Preconditioning of DPMSCs by CMMDA-231 reversed the inhibitory and stimulatory effects of CMMDA-231 on DPMSC adhesion and invasion, respectively. In addition, preconditioning with CMMDA-231 modulated DPMSC expression of genes with multiple functions, such as proliferation, adhesion and invasion. Moreover, preconditioned DPMSCs showed high expression of genes with anti-cancer properties. These data show the ability of DPMSCs to function normally in cancer environment while their preconditioning by this environment increases their anti-cancer therapeutic potential.

Materials and methods

Ethical approval and the collection of tissues (human placentae and umbilical cord tissues)

The institutional review board at KAIMRC (King Abdulla International Medical Research Centre) approved this study (IRBC/1187/17). Human placentae and umbilical cord tissues were obtained from uncomplicated pregnancies (38–40 weeks of gestation) of consented donors. Tissues were processed immediately. The clinical and experimental procedures were performed as per the guidelines and regulations of KAIMRC.

Isolation and culture of DPMSCs

DPMSCs were isolated and cultured in complete DPMSC culture medium [DMEM-F12 medium containing 10% FBS (fetal bovine serum, Life Technologies), 100 μg/mL of L-glutamate, and antibiotics (100 µg/mL streptomycin and 100 U/mL penicillin)] using our previously described method [1]. DPMSCs were incubated at 37 °C in a humidified chamber consisting of 5% CO₂ and 95% air, in a cell culture incubator. DPMSCs (passage 3) from a total of ten placentae were used.

Isolation and culture of HUVEC (human umbilical vein endothelial cells)

HUVEC were isolated and cultured in complete endothelial cell growth medium (Catalogue number PCS-100-041™, ATCC, Manassas, VA, USA) at 37 °C in a cell culture incubator using our previously published method [13]. HUVEC (passages 3–5) from ten umbilical cord tissues were used.

Cells (DPMSCs and HUVEC) were harvested using TrypLE™ solution (Life Technologies, Carlsbad, CA, USA), their viability was determined by Trypan blue, and then used in subsequent experiments.

DPMSC adhesion and proliferation using the xCELLigence system

Four DPMSC treatment groups were used in this study (Table 1 (i), Fig. 1). To produce CMMDA-231 [Conditioned medium harvested from the culture of breast cancer cell line, catalogue number MDA-MB-231 (ATCC^® HTB-26™), ATCC, Manassas, VA, USA] supernatant from MDA-231, culture was prepared as previously described [14]. Briefly, 1 × 10⁵ MDA-231 were cultured in a culture medium of DMEM-F12 containing 10% FBS, 100 μg/mL of L-glutamate, and antibiotics (above). Culture medium was changed every 48 h until 75% of cell confluency was achieved. Cells were fed with fresh culture medium for 72 h, and conditioned medium (CMMDA-231) was then collected by centrifugation.

Table 1.

DPMSC treatment groups used in this study

Group	Description
(i) DPMSC treatment groups used in the proliferation and adhesion experiments
1	DPMSC cultured alone
2	DPMSCs cultured with 1–25% CMMDA-231
3	DPMSCs cultured with 25% CMMDA-231 [25 (in)]
4	DPMSCs precultured with 25% CMMDA-231 for 72 h [pre (25)], and DPMSCs were then harvested and used
(ii) DPMSC treatment groups used in the migration experiments
1	DPMSC cultured alone
2	DPMSCs cultured with with 25% CMMDA-231 [25 (in)] in the upper chamber
3	DPMSCs precultured with 25% CMMDA-231 for 72 h [pre (25)], and DPMSCs were then harvested and seeded in the upper chamber
(iii) DPMSC treatment groups used in the invasion experiments
1	DPMSCs were added to the monolayer of endothelial cells
2	DPMSCs were added to the monolayer of endothelial cells in the presence of 25% CMMDA-231 [25 (in)]
3	DPMSCs precultured with 25% CMMDA-231 for 72 h [pre (25)], and DPMSCs were then harvested and added to the monolayer of endothelial cells

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CMMDA-231: conditioned medium experiment

Fig. 1 — A–D DPMSC culture system used in this study. DPMSCs were seeded on a surface of 16-well plate in the xCELLigence system containing complete DPMSC culture medium alone (Untreated DPMSC), or with 1–25% CMMDA-231 [conditioned medium (CM) obtained from the culture of MDA-231], or with 25% CMMDA-231 [25 (in)], and pre (25) [DPMSCs precultured with 25% CMMDA-231 for 72 h], and DPMSCs were then harvested and seeded in the well of 16-well plate in xCELLigence. In all culture systems, cells were incubated at 37 °C in a cell culture incubator. E–G DPMSC proliferation in response to various concentrations (0–25%) of CMMDA-231 using the xCELLigence system. At 24 h, and as compared to untreated DPMSCs, DPMSC proliferation was not significantly changed in response to 1, 5 and 10% CMMDA-231 (p > 0.05), but significantly reduced in response to 25% CMMDA-231. In contrast, at 48 h, the proliferation of DPMSCs significantly reduced to 1, 5 and 25% CMMDA-231, but not to 10% CMMDA-231 (p > 0.05) as compared to untreated DPMSCs. At 72 h, DPMSC proliferation significantly reduced in response to 1 and 25% CMMDA-231, but not to 5 and 10% CMMDA-231 as compared to untreated DPMSCs, p > 0.05. H–J Reversibility of DPMSC proliferation. DPMSCs were initially cultured with 25% CMMDA-231 [25 (pre)] for 72 h, DPMSCs- pretreated with CMMDA-231 were then harvested and seeded on a surface of 16- well plate in a complete DPMSC culture medium, and their proliferation was then compared to untreated DPMSCs or DPMSCs cultured in a complete DPMSC culture medium containing 25% CMMDA-231 [25 (in)] using the xCELLigence system. At 24, 48 and 72 h, and as compared to untreated DPMSCs, the proliferation of DPMSCs cultured with 25% CMMDA-231 [25 (in)] significantly reduced. As compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)], the pretreatment of DPMSCs with 25% CMMDA-231 [25 (pre)] did not significantly change (p > 0.05) the proliferation of DPMSCs at 24 h, but it was significantly reduced at 48 and 72 h. Each experiment was performed in triplicate and repeated with five independent DPMSC (passage 3) preparations. *p < 0.05. Bars represent standard errors

The adhesion and proliferation of DPMSCs were evaluated using the xCELLigence system (RTCA-DP; Roche Diagnostics, Mannheim, Germany) as previously described [13, 15–17]. Briefly, 5 × 10³ DPMSCs (Table 1 (i), Fig. 1A–D) were seeded in a well of 16-well culture plates (Catalogue number 05469813001, E-Plate 16, Roche Diagnostics, Basel, Switzerland) containing complete DPMSC culture medium (Table 1 (i), Fig. 1). The culture plates were then placed in the xCELLigence system (RTCA-DP; Roche Diagnostics, Mannheim, Germany) at 37 °C in a cell culture incubator, and the cell index was automatically monitored. Data for cell adhesion (at 2 h) and proliferation (24–72 h) was measured as previously described [3, 13, 15–17]. Each experiment was performed in triplicate and repeated with five independent DPMSC (passage 3) preparations.

DPMSC migration using xCELLigence system

Cell treatment groups (Table 1 (ii), Fig. 3) were used to evaluate DPMSC migration using the xCELLigence system, and CIM-16-well plates (Catalogue number 05665825001, Roche Diagnostics, Basel, Switzerland) as previously described [13, 15–17]. Briefly, 1 × 10⁴ DPMSCs were seeded in the upper chamber of the plate, and automatically monitored for 24 h by the xCELLigence system. The data was expressed as a cell index value [13, 15–17]. DPMSC migration with, and without 30% FBS served as a positive and negative control, respectively. Each experiment was performed and repeated as described above.

DPMSC invasion under the effect of CMMDA-231

Using the xCELLigence system, we evaluated the effect of CMMDA-231 on the ability of DPMSCs to invade through a monolayer of endothelial cells. Briefly, 2.5 × 10⁴ HUVEC were seeded in complete endothelial cell growth medium in a 16-well culture E-Plate (as described above) until they reached a growth plateau (20 h). Different treatments of 1 × 10⁴ DPMSCs (Table 1 (iii)) were then added to this monolayer of endothelial cells. After 10 h, data for the invasion was recorded and expressed as cell index (mean ± standard error). The rate of cell invasion was determined by calculating the normalized cell index at pausing time (20 h) of HUVEC growth.

Gene expression by real-time polymerase chain reaction (RT-PCR)

DPMSC expression of 84 genes relating to Human Cytokines and Chemokines (Catalogue number PAHS-150Z, Qiagen, Hilden, Germany) was identified using the RT-PCR system [15, 17–19]. Total RNA was extracted from DPMSCs [untreated DPMSCs, DPMSCs pretreated with 25% CMMDA-231 for 72 h, and DPMSCs pretreated with 25% CMMDA-231 for 72 h and then re-cultured alone for 72 h] and cDNA was synthesized and used in a QuantiTect Primer Assay (Qiagen, Hilden, Germany). The real-time polymerase chain reaction (RT-PCR) was performed in triplicate on the CFX96 real-time PCR detection system (BIO-RAD, Hercules, CA, USA), and the data was analyzed by calculating ΔΔ⁻² values. The results are expressed as fold change expression as compared to control Relative expression of house-keeping genes were used as internal controls. Experiments were performed in triplicate and repeated three times using DPMSCs prepared from three independent placentae.

Statistical analysis

GraphPad Prism 5 was used to analyze data using non-parametric tests (Mann–Whitney U and Kruskal–Wallis). Data were deemed statistically significant if p < 0.05.

Results

CMMDA-231 reduced DPMSC proliferation

DPMSCs were used to examine the effect of CMMDA-231 on DPMSC proliferation by the xCELLigence system. At 24 h, and as compared to untreated DPMSCs, DPMSC proliferation did not significantly change in response to 1, 5, and 10% CMMDA-231 (p > 0.05), but significantly reduced (p < 0.05) in response to 25% CMMDA-231 (Fig. 1E). In contrast, at 48 h, the proliferation of DPMSCs significantly reduced (p < 0.05) in response to 1, 5 and 25% CMMDA-231, but not to 10% CMMDA-231 as compared to untreated DPMSCs (Fig. 1F). At 72 h, DPMSC proliferation significantly reduced (p < 0.05) in response to 1 and 25% CMMDA-231, but not to 5 and 10% CMMDA-231 (p > 0.05) as compared to untreated DPMSCs (Fig. 1G).

The viability of DPMSCs treated with CMMDA-231 (1–25%) for all examined time points was 95%. In some experiments, DPMSCs were cultured with 50 and 100% CMMDA-231, and their viability at these two concentrations was > 90%. Based on the results obtained above, the exposure time of 72 h and CMMDA-231 at 25% were selected to evaluate the effect of CMMDA-231 on DPMSC functions (proliferation, adhesion, migration, and invasion).

Reversibility of DPMSC proliferation under the effect of CMMDA-231

To evaluate the reversibility of the inhibitory effect of CMMDA-231 on DPMSC proliferation, cells were intially cultured with 25% CMMDA-231 [25 (pre)] for 72 h, harvested, and then their proliferation as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)] was determined using the xCELLigence system.

At 24, 48 and 72 h, and as compared to untreated DPMSCs, the proliferation of DPMSCs cultured with 25% CMMDA-231 [1 (in)] or precultured with 25% CMMDA-231 for 72 h [25 (pre)] significantly reduced (p < 0.05) while the pretreatment of DPMSCs with 25% CMMDA-231 for 72 h [25 (pre)] had no significant effect (p > 0.05) on their proliferation as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)] at 24 h, but was significantly reduced (p < 0.05) at 48 and 72 h (Fig. 1H–J).

CMMDA-231 effect on DPMSC adhesion

To evaluate the effect of CMMDA-231 on DPMSC adhesion, the xCELLigence system was used. At 2 h, and as compared to untreated DPMSCs, the adhesion of DPMSCs cultured with 25% CMMDA-231 [1 (in)], but not precultured with 25% CMMDA-231 for 72 h [25 (pre)] significantly reduced (p < 0.05). In addition, the pretreatment of DPMSCs with 25% CMMDA-231 for 72 h [25 (pre)] significantly increased (p < 0.05) DPMSC adhesion as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)] at 2 h (Fig. 2).

Fig. 2 — DPMSC adhesion in response to CMMDA-231 or after removing the effects of CMMDA-231. DPMSCs were initially cultured with CMMDA-231 for 72 h and then cultured alone in an adhesion assay using the xCELLigence system. At 2 h, and as compared to untreated DPMSCs, the adhesion of DPMSCs significantly reduced in response to 25% CMMDA-231 [25 (in)]. The pretreatment of DPMSCs with 25% CMMDA-231 [25 (pre)] did not significantly change (p > 0.05) the adhesion of DPMSCs at 2 h as compared to untreated DPMSCs, but as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)], the DPMSC adhesion significantly increased. Each experiment was performed in triplicate and repeated with five independent DPMSC (passage 3) preparations. *p < 0.05. Bars represent standard errors

CMMDA-231 effect on DPMSC migration

We also evaluated the effect of CMMDA-231 on the migration of DPMSCs cultured alone or with 25% CMMDA-231 [25 (in)] or precultured with 25% CMMDA-231 [25 (pre)] in the upper chamber of the plate using the xCELLigence system. At 24 h, the migration of DPMSCs cultured with 25% CMMDA-231 [25 (in)] or precultured with 25% CMMDA-231 [25 (pre)] did not significantly change (p > 0.05) as compared to untreated DPMSCs (Fig. 3). The pre-culture of DPMSCs with 25% CMMDA-231 [25 (pre)] did not significantly change (p > 0.05) the migration of DPMSCs at 24 h and as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)] (Fig. 3D).

CMMDA-231 effect on DPMSC invasion of HUVEC

We also evaluated the effect of CMMDA-231 on DPMSC invasion of HUVEC by the xCELLigence system. Invasion is defined as the infiltration of HUVEC monolayer by DPMSCs which causes detachment of HUVEC that results in increased adhesion of DPMSCs associated with elevation in the cell index. At 10 h treatment and as compared to untreated DPMSCs, the invasion of HUVEC monolayer by DPMSCs cultured in 25% CMMDA-231 was significantly increased (p < 0.05) (Fig. 4), but the invasion of HUVEC monolayer by DPMSCs pretreated with 25% CMMDA-231 for 72 h [25 (pre)] did not significantly change (p > 0.05) as compared to DPMSCs cultured in 25% CMMDA-231 [25 (in)] (Fig. 4). In addition, pretreatment of DPMSCs with 25% CMDA-231 for 72 h [25 (pre)] significantly reduced (p < 0.05) DPMSC invasion of HUVEC monolayer as compared to DPMSCs cultured in 25% CMMDA-231 [25 (in)] (Fig. 4).

Fig. 4 — Effects of CMMDA-231 on DPMSC invasion through HUVEC monolayer. DPMSC invasion was examined by adding DPMSCs to a monolayer of HUVEC, and the invasion of DPMSCs through HUVEC monolayer was then assessed by the xCELLigence system. Invasion is defined as infiltration of HUVEC monolayer by DPMSCs which causes detachment of HUVEC resulting in increased adhesion of DPMSCs leading to elevated cell index. At 10 h and as compared to untreated DPMSCs, the invasion of DPMSCs cultured with 25% CMMDA-231 [25 (in)] significantly increased. The pretreatment of DPMSCs with 25% CMMDA-231 did not significantly change (p > 0.05) the invasion of DPMSCs as compared to untreated DPMSCs, but as compared to DPMSCs cultured with 25% CMMDA-231 [25 (in)], the invasion of DPMSCs significantly reduced. Each experiment was performed in triplicate and repeated with five independent DPMSC (passage 3) preparations. *p < 0.05. Bars represent standard errors

CMMDA-231 modulated the expression of genes important in DPMSC functions

The RT-PCR results show that 25% CMMDA-231 modulated the expression of many genes in DPMSCs (Tables 2, 3, 4, 5, 6).

Table 2.

MDA-231 modulated DPMSC expression of genes with pro-proliferative and anti-proliferative properties

No.	Gene symbol	Gene full name	CMDPMSC mean ΔΔ⁻² values	Pre-CMDPMSC mean ΔΔ⁻² values	Fold change (Pre-CMDPMSC vs. CMDPMSC) p < 0.05		Biological activities
1	CCL2	C-C motif chemokine ligand 2	239.78	2.10	114.18 Fold	↓	Promotes proliferation [36]
2	CCL18	C-C motif chemokine ligand 18	9.33	2.27	4.11 Fold	↓	Promotes proliferation [37]
3	CCL19	C-C motif chemokine ligand 19	474.38	8.69	54.58 Fold	↓	Promote proliferation
4	CCL20	C-C motif chemokine ligand 20	432.53	2.30	188.05 Fold	↓	Promotes proliferation [38]
5	IL-4	Interleukin-4	711.43	24.60	28.91 Fold	↓	Promotes proliferation [39]
6	IL-6	Interleukin-6	2.96	12.02	4.06 Fold	↑	Promotes proliferation [40]
7	IL-7	Interleukin-7	1.92	0.37	5.18 Fold	↓	Promotes proliferation [41]
8	IL-16	Interleukin-16	87.96	1.37	64.20 Fold	↓	Promotes proliferation [42]
9	CSF2	Colony stimulating factor 2	4.05	1.31	3.09 Fold	↓	Promotes proliferation [43]
10	LTA	Lymphotoxin alpha	19.17	3.23	5.93 Fold	↓	Promotes proliferation [44]
11	THPO	Thrombopoietin	4.33	1.49	2.90 Fold	↓	Promotes proliferation [45]
12	TNF	Tumor necrosis factor	2.85	1.40	2.03 Fold	↓	Promotes proliferation [46]
13	VEGFA	Vascular endothelial growth factor A	2.92	1.10	2.65 Fold	↓	Promotes proliferation [47]
14	CCL13	C-C motif chemokine ligand 13	0.86	2.78	3.23 Fold	↑	Promotes proliferation [95]
15	CCL24	C-C motif chemokine ligand 24	0.50	2.35	4.70 Fold	↑	Promotes proliferation [96]
16	CXCL16	C-X-C motif chemokine ligand 16	0.50	86.88	173.76 Fold	↑	Promotes proliferation [97]
17	CNTF	Ciliary neurotrophic factor	1.25	2.41	1.92 Fold	↑	Promotes proliferation [98]
18	CSF1	Colony stimulating factor 1	0.32	1.67	5.21 Fold	↑	Promotes proliferation [85]
19	BMP2	Bone morphogenetic protein 2	0.90	1.65	1.83 Fold	↑	Promotes proliferation [99]
20	GBI	Glucose-6-phosphate isomerase	0.55	2.80	5.09 Fold	↑	Promote proliferation [100]
21	IL-1RN	Interleukin-1 receptor antagonist	0.69	1.83	2.65 Fold	↑	Inhibits proliferation [48]
22	IL-11	Interleukin-11	29.50	12.60	2.34 Fold	↓	Inhibits proliferation [49]
23	IL-24	Interleukin-24	3.60	1.46	2.46 Fold	↓	Inhibits proliferation [50]
24	IFNγ	Interferon gamma	0.0003	4.96	16,533 Fold	↑	Inhibits proliferation [51]

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CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h). Pre-CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h, and were then re-cultured alone for another 72 h)

Table 3.

MDA-231 modulated DPMSC expression of genes with adhesive, migratory and invasive properties

No.	Gene symbol	Gene full name	CMDPMSC mean ΔΔ⁻² values	Pre-CMDPMSC mean ΔΔ⁻² values	Fold change (Pre-CMDPMSC vs. CMDPMSC) p < 0.05		Biological activities
1	BMP2	Bone morphogenetic protein 2	0.90	1.65	1.83 Fold	↑	Promotes adhesion [55]
2	CX3CL1	Chemokine (C-X3-C motif) ligand 1	0.000079	0.0099	125.31 Fold	↑	Promotes adhesion [56]
3	VEGFA	Vascular endothelial growth factor A	2.92	1.10	2.65 Fold	↓	Promotes adhesion [101]
4	CCL3	C-C motif chemokine ligand 3	5.74	15.94	2.77 Fold	↑	Promote migration [65]
5	CCL18	C-C motif chemokine ligand 18	9.33	2.27	4.11 Fold	↓	Promotes migration [57]
6	CXCL12	C-X-C motif chemokine ligand 12	7.41	1.80	4.11 Fold	↓	Promotes migration [58]
7	CXCL5	C-X-C motif chemokine ligand 5	4.78	40.89	8.55 Fold	↑	Promotes migration [59]
8	IL-4	Interleukin-4	711.43	24.60	28.91 Fold	↓	Promotes migration [60]
9	IL-11	Interleukin-11	29.50	12.60	2.34 Fold	↓	Promotes migration [49]
10	IL-16	Interleukin-16	87.96	1.37	64.20 Fold	↓	Promotes migration [61]
11	IL-24	Interleukin-24	3.60	1.46	2.46 Fold	↓	Inhibits migration [62]
12	TNF	Tumor necrosis factor	2.85	1.40	2.03 Fold	↓	Promotes migration [63]
13	VEGFA	vascular endothelial growth factor A	2.92	1.10	2.65 Fold	↓	Promotes migration [47]
14	BMP2	Bone morphogenetic protein 2	0.90	1.65	1.83 Fold	↑	Promotes migration [64]
15	CCL2	C-C motif chemokine ligand 2	239.78	2.10	114.18 Fold	↓	Promotes invasion [66]
16	CCL18	C-C motif chemokine ligand 18	9.33	2.27	4.11 Fold	↓	Promotes invasion [37]
17	CCL20	C-C motif chemokine ligand 20	432.53	2.30	188.05 Fold	↓	Promotes invasion [38]
18	CXCL12	C-X-C motif chemokine ligand 12	7.41	1.80	4.11 Fold	↓	Promotes invasion [58]
19	IL-6	Interleukin-6	2.96	12.02	4.06 Fold	↑	Promotes invasion [67]
20	IL-11	Interleukin-11	29.50	12.60	2.34 Fold	↓	Inhibits invasion [69]
21	VEGFA	Vascular endothelial growth factor A	2.92	1.10	2.65 Fold	↓	Promotes invasion [68]
22	CCL13	C-C motif chemokine ligand 13	0.86	2.78	3.23 Fold	↑	Promotes invasion [95]
23	CCL24	C-C motif chemokine ligand 24	0.50	2.35	4.70 Fold	↑	Promotes invasion [96]
24	CXCL5	C-X-C motif chemokine ligand 5	4.78	40.89	8.55 Fold	↑	Promotes invasion [59]
25	CXCL16	C-X-C motif chemokine ligand 16	0.50	86.88	173.76 Fold	↑	Promotes invasion [97]
26	IL-24	Interleukin-24	3.60	1.46	2.46 Fold	↓	Inhibits invasion [62]
27	BMP2	Bone morphogenetic protein 2	0.90	1.65	1.83 Fold	↑	Promotes invasion [99]

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CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h). Pre-CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h, and were then re-cultured alone for another 72 h)

Table 4.

MDA-231 modulated DPMSC expression of genes with inflammatory properties

No.	Gene symbol	Gene full name	CMDPMSC mean ΔΔ⁻² values	Pre-CMDPMSC mean ΔΔ⁻² values	Fold change (Pre-CMDPMSC vs. CMDPMSC) p < 0.05		Biological activities
1	CCL3	C-C motif chemokine ligand 3	5.74	15.94	2.77 Fold	↑	Promotes inflammation [70]
2	CCL13	C-C motif chemokine ligand 13	0.86	2.78	3.23 Fold	↑	Promotes inflammation [71]
3	CXCL9	C-X-C motif chemokine ligand 9	2.49	19.14	7.68 Fold	↑	Promotes inflammation [72]
4	CX3CL1	Chemokine (C-X3-C motif) ligand 1	0.000079	0.0099	125.31 Fold	↑	Promotes inflammation [56]
5	IL-12A	Interleukin-12A	0.64	6.10	9.53 Fold	↑	Promotes inflammation [73]
6	IL-18	Interleukin-18	1.31	2.29	1.74 Fold	↑	Promotes inflammation [74]
7	BMP2	Bone morphogenetic protein 2	0.90	1.65	1.83 Fold	↑	Promotes inflammation [75]
8	IL-11	Interleukin-11	29.50	12.60	2.34 Fold	↓	Inhibits inflammation [76]
9	CCL2	C-C motif chemokine ligand 2	239.78	2.10	114.18 Fold	↓	Promotes inflammation [77
10	CCL19	C-C motif chemokine ligand 19	474.38	8.69	54.58 Fold	↓	Promotes inflammation [78]
11	CXCL2	C-X-C motif chemokine ligand 2	1576997	9071	173.85 Fold	↓	Promotes inflammation [79]
12	IL-7	Interleukin-7	1.92	0.37	5.18 Fold	↓	Promotes inflammation [80]
13	IL-12B	Interleukin-12B	19386	12.80	1514.53	↓	Promotes inflammation [73]
14	IL-16	Interleukin-16	87.96	1.37	64.20 Fold	↓	Promotes inflammation [81]
15	LTA	Lymphotoxin alpha	19.17	3.23	5.93 Fold	↓	Promotes inflammation [82
16	TNF	Tumor necrosis factor	2.85	1.40	2.03 Fold	↓	Promotes and inhibits inflammation [83]
17	CNTF	Ciliary neurotrophic factor	1.25	2.41	1.92 Fold	↑	Inhibits inflammation [84]
18	CSF1	Colony stimulating factor 1	0.32	1.67	5.21 Fold	↑	Inhibits inflammation [85]
19	TGFB2	Transforming growth factor-β-2	0.25	1.69	6.76 Fold	↑	Inhibits inflammation [86

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CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h). Pre-CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h, and were then re-cultured alone for another 72 h)

Table 5.

MDA-231 modulated DPMSC expression of genes with protumorigenic and antitumor activities

No.	Gene symbol	Gene full name	CMDPMSC mean ΔΔ⁻² values	Pre-CMDPMSC mean ΔΔ⁻² values	Fold change (Pre-CMDPMSC vs. CMDPMSC) p < 0.05		Biological activities
1	CCL3	C-C motif chemokine ligand 3	5.74	15.94	2.77 Fold	↑	Antitumor activity [87]
2	IFNA2	Interferon alpha 2	31.61	4.34	7.28 Fold	↓	Antitumor activity [88]
3	IFNγ	Interferon gamma	0.0003	4.96	16,533 Fold	↑	Antitumor Activity [51]
4	IL1RN	Interleukin-1 receptor antagonist	0.69	1.83	2.65 Fold	↑	Antitumor activity [48]
5	IL-24	Interleukin-24	3.60	1.46	2.46 Fold	↓	Antitumor activity [50]
6	IL-4	Interleukin-4	711.43	24.60	28.91 Fold	↓	Antitumor activity [89]
7	LTA	Lymphotoxin alpha	19.17	3.23	5.93 Fold	↓	Antitumor activity [90]
8	FASLG	Fas ligand	1.38	0.77	1.79 Fold	↓	Antitumor activity [91]
9	IL-6	Interleukin-6	2.96	12.02	4.06 Fold	↑	Protumorigenic activity [92]
10	IL-7	Interleukin-7	1.92	0.37	5.18 Fold	↓	Protumorigenic activity [93]
11	IL16	Interleukin 16	87.96	1.37	64.20 Fold	↓	Protumorigenic activity [94]
12	TNF	Tumor necrosis factor	2.85	1.40	2.03 Fold	↓	Protumorigenic activity [83]
13	VEGFA	Vascular endothelial growth factor A	2.92	1.10	2.65	↓	Protumorigenic activity [47]

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CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h). Pre-CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h, and were then re-cultured alone for another 72 h)

Table 6.

MDA-231 modulated the expression of genes in DPMSCs

No.	Gene symbol	CMDPMSC mean ΔΔ⁻² values	Pre-CMDPMSC mean ΔΔ⁻² values	Fold change (Pre-CMDPMSC vs. CMDPMSC)
1	CCL5	0.77	1.02	Fold change is not statistically significant, p > 0.05
2	CCL7	2.30	2.46
3	CCL11	0.16	0.16
4	CCL21	0.98	1.15
5	CXCL10	0.91	0.84
6	XCL1	1.27	1.26
7	IL1A	1.05	1.45
8	IL1B	1.60	2.24
9	IL-5	0.95	1.00
10	IL-8	0.59	0.85
11	IL-10	1.36	1.09
12	IL-13	1.37	1.77
13	IL-15	1.20	0.97
14	IL-23A	1.10	1.07
15	IL-27	2.25	1.81
16	LIF	2.73	2.28
17	LTB	0.79	1.36
18	MIF	24.20	24.73
19	CD40LG	1.31	1.27
20	CSF3	1.67	2.00
21	MSTN	0.76	0.95
23	NODAL	2.40	1.13
24	OSM	1.30	1.622
25	PPBP	1.42	1.37
26	SPP1	0.88	1.32
27	TNFRSF11B	2.59	5.51
28	TNFSF10	1.49	3.04
29	TNFSF11	0.93	1.47
30	TNFSF13B	0.50	1.63
31	ADIPOQ	1.36	1.55
32	BMP4	1.03	1.31
33	BMP6	1.43	2.10
34	BMP7	1.46	1.77
35	C5	1.47	2.35

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CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h). Pre-CMDPMSC (DPMSCs were cultured with 25% MDA-231 for 72 h, and were then re-cultured alone for another 72 h)

Discussion

Previously, we have reported the phenotypic and functional properties of DPMSCs [1], and their interaction with NK cells [3]. We showed that DPMSCs can induce NK cell cytotoxic activity against cancer cells [3]. This property makes DPMSCs as potential therapeutic agent for cancer. Cancer is an inflammatory disease that is characterized by a hostile microenvironment, which supports the growth and progression of tumor cells [20]. This microenvironment contains inflammatory molecules including cytokines, chemokines, growth factors that modulate the functions of transplanted MSCs [6–11]. Therefore, for successful use of DPMSCs as an anti-cancer therapeutic agent, we studied the effects of CMMDA-231 on DPMSC functional and phenotypic properties.

First, we report the survival of DPMSCs under a continuous exposure to high concentration (up to 100%) of CMMDA-231. MDA-231 secretes several inflammatory molecules with ability to induce cellular injury, such as IL-1β, IL-6, IL-8, and matrix metalloproteinases (MMPs) [21–28]. For example, the culture of pancreatic beta-cells with IL-6 induces their apoptotic death [27].

Survival of DPMSCs in such harsh tumor environment could be attributed to their placental niche, where they are usually exposed to high levels of oxidative stress and inflammatory mediators during normal pregnancy [29, 30]. Therefore, DPMSCs might have acquired biological characteristics to resist death induced by inflammatory molecules.

The ability of DPMSCs to counteract injury induced by CMMDA-231 was further supported by maintaining their functional activities. DPMSCs proliferated in response to CMMDA-231 (Fig. 1). However, they showed a reduction in their proliferation (Fig. 1). This data may suggest that it is safe to use DPMSCs as previously reported for other types of MSCs. It was shown that the transplantation of human bone marrow derived MSCs (BMMSCs) does not form malignant tumor [31]. Therefore, the use of DPMSCs as therapeutic agent is probably safe, but requires further confirmation in animal studies before their applications in patients.

MDA-231 secretes IL-10, plasminogen activator inhibitor type 1 (PAI-1), and parathyroid hormone-related protein (PTHrP) [22, 32, 33]. These molecules have antiproliferative properties [33–35]. Therefore, the antiproliferative effect of CMMDA-231 on DPMSCs is possibly mediated by these molecules. In this study, preconditioning of DPMSCs with CMMDA-231 reduced and increased their expression of pro-proliferative [36–47], and antiproliferative [48–51] genes, respectively, Table 2. Therefore, these genes may mediate the anti-proliferative effect of MDA-231 on DPMSCs. However, a future mechanistic study is essential to elucidate this finding further.

After transplanting MSCs into patients, MSCs must function in a disease environment where they is high level of oxidative stress and inflammatory mediators [52, 53]. In this study, CMMDA-231 reduced DPMSC adhesion. IL-10 usually reduces cell adhesion [54], and therefore, IL-10 in the conditioned medium of MDA-231, may act on DPMSCs to reduce their adhesion. Preconditioning of DPMSCs with CMMDA-231 reversed this inhibitory effect of CMMDA-231 on DPMSC adhesion (Fig. 2). This reversible effect of MDA-231 on DPMSC adhesion is probably mediated by inducing the expression of adhesive genes (i.e., BMP2 and CX3CL1) [55, 56] in preconditioned DPMSCs (Table 3). In contrast, DPMSC migration was not changed by CMMDA-231 (Fig. 3), but phenotypically, CMMDA-231 modulated DPMSC expression of genes with migratory properties [47, 49, 57–65] (Table 3). However, these genes are also involved in another cellular functions, such as proliferation, adhesion, invasion, inflammation, pro-tumour and antitumor activities. Therefore these genes may mediate another functional activities of DPMSCs.

MSCs must also penetrate the endothelial cell barrier in order to reach their cellular targets. CMMDA-231 promoted DPMSC invasion on a reversible effect (Fig. 4). CMMDA-231 also modulated DPMSCs expression of invasive genes [37, 38, 58, 59, 60, 67–69], Table 3. However, the molecular pathway involved in MDA-231 modulating DPMSC invasion needs to be further investigated.

Phenotypically, CMMDA-231 modulated DPMSCs expression of genes with inflammatory [57, 70–76], anti-inflammatory [73, 77–86], anti-tumorigenic and pro-tumorigenic properties [47, 48, 50, 51, 83, 87–94] (Tables 4, 5). These phenotypic data show the double-edged sword properties of DPMSCs as we previously reported for MSCs isolated from the decidua basalis region of human term placenta [15]. Importantly, DPMSCs show anti-cancer phenotypic properties, which further confirms our previous report of DPMSCs on the anti-cancer activity of NK cells [3].

In conclusion, this study shows the functional activities of DPMSCs in response to cancer environment, and their biosafety. DPMSCs were able to perform invasion activity, and thus demonstrating their engraftment property. CMMDA-231 also modulated the phenotypic features of DPMSCs particularly their anti-cancer property. These data show the suitability of using DPMSCs in treating cancers. However, future studies will reveal the mechanism underlying the effects of MDA-231 on DPMSC functions, and confirm their anti-cancer therapeutic potential.

Acknowledgements

We appreciate the staff and patients of King Abdul Aziz Medical City for providing us with placentae. MHA proposed and supervised the project. MHA designed the experiments. EB performed the experiments. MHA, EB and TK analysed the data. MHA wrote the manuscript. MHA, FMA, TK, and SAM contributed to data analysis and interpretation of results. All authors reviewed the manuscript. This study was supported by Grants from KAIMRC (Grant No. RC12/133).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

IRB of KAIMRC approved this study (IRBC/1187/17). Samples (Placentae and umbilical cords) were obtained after signing consent forms.

Footnotes

M. H. Abumaree—deceased.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

F. M. Abomaray, Email: fawaz.abomaray@ki.se

M. H. Abumaree, Email: mohamedabumaree@hotmail.com, Email: abumareem@ksau-hs.edu.sa

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PERMALINK

Cancer Conditioned Medium Modulates Functional and Phenotypic Properties of Human Decidua Parietalis Mesenchymal Stem/Stromal Cells

E Bahattab

T Khatlani

F M Abomaray

S A Messaoudi

M H Abumaree

Abstract

Background:

Methods:

Results:

Conclusion:

Introduction

Materials and methods

Ethical approval and the collection of tissues (human placentae and umbilical cord tissues)

Isolation and culture of DPMSCs

Isolation and culture of HUVEC (human umbilical vein endothelial cells)

DPMSC adhesion and proliferation using the xCELLigence system

Table 1.

Fig. 1.

DPMSC migration using xCELLigence system

Fig. 3.

DPMSC invasion under the effect of CMMDA-231

Gene expression by real-time polymerase chain reaction (RT-PCR)

Statistical analysis

Results

CMMDA-231 reduced DPMSC proliferation

Reversibility of DPMSC proliferation under the effect of CMMDA-231

CMMDA-231 effect on DPMSC adhesion

Fig. 2.

CMMDA-231 effect on DPMSC migration

CMMDA-231 effect on DPMSC invasion of HUVEC

Fig. 4.

CMMDA-231 modulated the expression of genes important in DPMSC functions

Table 2.

Table 3.

Table 4.

Table 5.

Table 6.

Discussion

Acknowledgements

Compliance with ethical standards

Conflict of interest

Ethical statement

Footnotes

Contributor Information

References

ACTIONS

PERMALINK

RESOURCES

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