Table 1.

Possible ADSC-based therapeutic strategies for ovarian cancer Abbreviations: ADSC: adipose-derived stem cells; CM: conditioned medium; Exo: exosomes; MV: microvesicles; PTX: Paclitaxel; IRI: irinotecan.

Authors and Year of Publication	Possible Therapeutic Agent	Possible Mechanism of Action	Experimental Model	Results	Reference
Direct Cellular Inhibition
Cho, J.A., 2009	CM from Hyperthermia-conditioned ADSCs	Reduced expression of mRNAs for MDR1 and Bfl-1 (Bcl-2 family). Increased expression of mRNA coding for TNF-R	In vitro on SKOV3 cell cultures	CM from Hyperthermia-treated ADSCs had enhanced suppressive effect on tumor progression and malignancy compared to normal ADSC controls	[71]
Reza, A.M.M.T., 2016	CM from ADSCs	Exo-mediated reduction in expression of anti-apoptotic BCL-2 and increased levels of pro-apoptotic BAX, CASP9, and CASP3, exo-miRNAs-mediated CDK dysregulation	In vitro on SKOV3 and A2780 cell cultures	reduced proliferation, cell viability, wound-repair capacity, and colony formation ability of A2780 and SKOV-3 ovarian cancer cells	[62]
Khalil, C., 2019	ADSCs from subcutaneous lipoaspirate and their CM	Decrease in MMP-2, MMP-9, and CA-125 mRNA expression. The cytokine profile was modified with an increase in IL-4 and IL-10 and an IL-6 reduction.	In vitro, co-culture of OVCAR3, CAOV3, IGROV3 and SKOV3 with ADSCs and ADSC-CM	Reduction in the level of CA-125 and LDH, along with increased apoptosis. Significant decreased of the invasive capacity and aggressiveness of cancer cell lines	[72]
Szyposzynska, A., 2020	MVs from immortalized ADSCs	Reduction in the tumor cell secretion of pro-tumorigenic cytokines, such as IL-6, IL-8, GRO-alpha, and VEGF. Increased levels of tumor-suppressive cytokines such as IL-1ra, IL-2, IL-2Ra, IL-12-p40, IL12-p70, IL-15, and IFN-γ	In vitro on ES-2 and OAW-42 cell culture	MVs were efficiently internalized by both cell types with a decrased metabolic rate and an increased apoptosis. Increased expression of anti-tumor factors in both cell lines compared to control	[73]
Drug Preloaded ADSCs
Melzer, C., 2020	Immortalized ADSCs	ADSCs incubated with taxol and epirubicin internalized the drugs and released drug loaded Exo in the extracellular space with higher cytotoxic activity that the free drugs	In vitro SKOV3 cell lines. In vivo, subcutaneous tumor in SCID mice	Drug-loaded exosomes have a higher cytotoxic effect at lower concentrations than free taxol in vitro. Higher tumor-suppressing capacity, when administered IV in the animal model.	[74]
Borghese, C., 2020	PTX primed ADSCs and PTX-primed ADSC-CM	ADSCs primed with PTX could internalize and release the drug in the extracellular space.	In vitro, SKOV3 2D cultures and 3D spheroid systems	ADSCs primed with PTX and their CM demonstrated a similar tumor-inhibiting capacity. Cytotoxicity was higher than with free PTX and could overcome PTX resistance, both with 2D and 3D culture systems.	[75]
ADSCs in Enzyme/Prodrug Systems
Toro, L., 2016	yCD:UPRT-expressing ADSCs	Adenoviral transduction of yCD:UPRT gene in the ADSCs. ADSC-expressed yCD:UPRT converted 5-FC to 5-FU with high tumor cytotoxic effects	SKOV3 and A2780 cell cultures in vitro. In vivo, intraperitoneal ovarian tumor in nude mice	yCD:UPRT-ADSCs/5-FC combination was efficacious both in 2D and 3D culture systems and both on SKOV3 and A2780 cells. Long-term tumor-free survival in 33% of the animals..	[76]
Malekshah, O.M., 2019	shCE2-expressing ADSCs	Plasmid trasfection of ADSCs with shCE2 gene. Co-administration of IRI and shCE2-expressing ADSCs. Localization of the ADSCs in the tumor site and conversion of IRI to its highly cytotoxic form SN-38, is carried out by the ADSC-secreted shCE2	In vitro, in OVASC-1 cells. In vivo, intraperitoneal ovarian tumor in nude mice	IRI co-administered with shCE2-expressing ADSCs inhibited the proliferation of ALDH+, drug-resistant, ovarian cancer cells at lower concentrations IRI with shCE2-ADSCseradicated ovarian cancer in 80% of the mice, with reduced toxicity,	[77]
Yin, P.T., 2016	TRAIL-expressing ADSCs	Magnetic NP delivered into ADSCs a heat-inducible gene vector that encoded for TRAIL. As a result, mild magnetic hyperthermia-induced TRAIL expression in ADSCs end secretion in the tumor microenvironment	A2780 cell cultures in vitro. In vivo, intraperitoneal ovarian tumor in nude mice	TRAIL-ADSCs, efficiently killed ovarian tumor cells in vitro. Preferential ADSC homing in the tumor after intraperitoneal injection in a mouse model of metastatic ovarian cancer. Efficient TRAIL delivery and significant decrease in tumor volume.	[78]
Kuroki, L.M., 2017	TR3-expressing ADSCs	Adenoviral transduction of TRAIL-based molecule TR3. ADSC expretion of TR3 and secretion in the tumor microenvironment	OVCAR3 cell lines in vitro	Transduced ADSCs efficiently expressed TR3 and secreted it in the extracellular space. TR3-transduced ADSCs and their CM inhibited ovarian cancer cell growth in vitro.	[79]
ADSCs Combined with Oncolytic Virus
Mader, E.K., 2013	Measles virus infected ADSCs	ADSCs localized in the tumor stroma ad released the Measles virus with an oncolytic effect	SKOV3 cell cultures in vitro. In vivo, intraperitoneal ovarian tumor in nude mice	ADSCs efficiently delivered the Measles virus to the tumor stroma, obtaining a cancer-cytotoxic effect and significantly prolonged survival in the treated animals.	[80]