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Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24
Sujit K Bhutia1, Swadesh K Das, Belal Azab
1Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA.
Abstract:
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent "bystander" activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival.
Insights
Melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) effectively inhibits breast cancer stem cell growth and self-renewal by suppressing Wnt signaling. This therapy is safe for normal cells and shows potent bystander effects against distant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) possesses known antitumor properties.
- Cancer stem cells (CSCs) are crucial drivers of tumor initiation, metastasis, and recurrence.
- Targeting CSCs is a promising strategy for effective cancer eradication.
Purpose of the Study:
- To investigate the role of MDA-7/IL-24 in inhibiting the growth and self-renewal of breast cancer-initiating/stem cells.
- To elucidate the molecular mechanisms underlying MDA-7/IL-24's effects on CSCs.
- To evaluate the therapeutic potential of MDA-7/IL-24 in preclinical models.
Main Methods:
- Adenoviral delivery of MDA-7/IL-24 (Ad.mda-7) to breast CSCs and normal breast stem cells.
- Assessment of cell proliferation, apoptosis, and endoplasmic reticulum (ER) stress.
- Analysis of Wnt/β-catenin signaling pathway activity.
- Evaluation of Ad.mda-7 efficacy in a nude mouse xenograft model.
Main Results:
- Ad.mda-7 infection selectively reduced proliferation and induced apoptosis and ER stress in breast CSCs, sparing normal stem cells.
- MDA-7/IL-24 suppressed CSC self-renewal by inhibiting Wnt/β-catenin signaling; Wnt pathway reactivation promoted CSC survival.
- In vivo, Ad.mda-7 significantly inhibited tumor growth from CSCs and demonstrated bystander effects on distant tumors.
- Treatment led to decreased proliferation, angiogenesis, and CSC percentage in tumors.
Conclusions:
- MDA-7/IL-24 demonstrates selective toxicity towards breast CSCs while being safe for normal stem cells.
- Inhibition of Wnt/β-catenin signaling is a key mechanism for MDA-7/IL-24-mediated CSC death.
- MDA-7/IL-24 exhibits significant potential as a safe and effective therapeutic agent for eradicating cancer, including CSC populations.
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