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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Genetically engineered mesenchymal stromal cells producing TNFα have tumour suppressing effect on human melanoma
Silvia Tyciakova1, Miroslava Matuskova, Roman Bohovic
1Laboratory of Molecular Oncology, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia.
Background:
Mesenchymal stromal cells (MSC) are a promising tool for targeted cancer therapy due to their tumour-homing ability. Intrinsic resistance enables the MSC to longer tolerate therapeutic factors, such as prodrug converting enzymes, cytokines and pro-apoptotic proteins. Tumour necrosis factor alpha (TNFα) is known to be cytotoxic to a variety of cancer cells and exert a tumour-destructive capacity.
Methods:
MSC were retrovirally transduced to stable express an exogenous gene encoding the desired therapeutic agent hTNFα. The effect of a TNFα-producing adipose tissue-derived MSC (AT-MSC/hTNFα) was tested on the tumour cell lines of different origins: melanoma (A375), breast carcinoma (SKBR3, MDA-MB-231), colon carcinoma (HT29), ovarian carcinoma (SKOV3) and glioblastoma (U87-MG) cells. The tumour suppressing effect of AT-MSC/hTNFα on A375 melanoma xenografts was monitored in an immunodeficient mouse model in vivo.
Results:
Engineered AT-MSC are able to constitutively secrete human TNFα protein, induce apoptosis of tumour cell lines via caspase 3/7 activation and inhibit the tumour cell proliferation in vitro. Melanoma A375 and breast carcinoma SKBR3 cells were the most sensitive, and their proliferation in vitro was reduced by conditioned media produced by AT-MSC/hTNFα to 60% and 40%, respectively. The previously reported tumour supportive effect of AT-MSC on subcutaneous A375 melanoma xenograft growth was neutralised and suppressed by engineered AT-MSC stably producing hTNFα. When AT-MSC/hTNFα were coinjected with A375 melanoma cells, the tumour mass inhibition was up to 97.5%.
Conclusions:
The results of the present study demonstrate that tumour cells respond to hTNFα-based treatment mediated by genetically engineered AT-MSC/hTNFα both in vitro and in vivo.
Insights
Genetically engineered mesenchymal stromal cells (MSCs) secreting tumor necrosis factor alpha (TNFα) effectively target and destroy various cancer cells in vitro and in vivo. This novel approach neutralizes tumor growth, demonstrating significant potential for cancer therapy.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Cell Therapy
Background:
- Mesenchymal stromal cells (MSCs) possess inherent tumor-homing capabilities, making them suitable for targeted cancer therapies.
- MSCs exhibit resistance to therapeutic agents, allowing for sustained delivery of cytotoxic factors.
- Tumor necrosis factor alpha (TNFα) is a potent cytotoxic agent with demonstrated tumor-destructive potential.
Purpose of the Study:
- To engineer adipose tissue-derived MSCs (AT-MSCs) to stably express human TNFα (hTNFα) for cancer treatment.
- To evaluate the anti-tumor efficacy of engineered AT-MSC/hTNFα in various cancer cell lines in vitro.
- To assess the in vivo anti-tumor activity of AT-MSC/hTNFα in a melanoma xenograft mouse model.
Main Methods:
- Retroviral transduction of MSCs to achieve stable expression of hTNFα.
- In vitro assessment of AT-MSC/hTNFα on melanoma, breast, colon, ovarian, and glioblastoma cell lines.
- In vivo evaluation of AT-MSC/hTNFα in an immunodeficient mouse model with A375 melanoma xenografts.
Main Results:
- Engineered AT-MSCs constitutively secreted hTNFα, inducing apoptosis via caspase 3/7 activation and inhibiting tumor cell proliferation in vitro.
- Melanoma (A375) and breast carcinoma (SKBR3) cells showed the highest sensitivity to AT-MSC/hTNFα conditioned media.
- AT-MSC/hTNFα neutralized previously observed tumor-supportive effects of MSCs and significantly suppressed A375 melanoma xenograft growth, achieving up to 97.5% tumor mass inhibition when co-injected.
Conclusions:
- Genetically engineered AT-MSCs effectively deliver hTNFα to target tumor cells.
- The AT-MSC/hTNFα system demonstrates significant anti-tumor activity both in vitro and in vivo.
- This approach holds promise for developing novel cell-based cancer therapies leveraging the cytotoxic potential of TNFα.
