Abstract
Melanoma is the most aggressive form of skin cancer. Hypoxia is a feature of the tumor microenvironment that reduces efficacy of immuno- and chemotherapies, resulting in poor clinical outcomes. Lactococcus lactis is a facultative anaerobic gram-positive lactic acid bacterium (LAB) that is Generally Recognized as Safe (GRAS). Recently, the use of LAB as a delivery vehicle has emerged as an alternative strategy to deliver therapeutic molecules; therefore, we investigated whether L. lactis can target and localize within melanoma hypoxic niches. To simulate hypoxic conditions in vitro, melanoma cells A2058, A375 and MeWo were cultured in a chamber with a gas mixture of 5% CO2, 94% N2 and 1% O2. Among the cell lines tested, MeWo cells displayed greater survival rates when compared to A2058 and A375 cells. Co-cultures of L. lactis expressing GFP or mCherry and MeWo cells revealed that L. lactis efficiently express the transgenes under hypoxic conditions. Moreover, multispectral optoacoustic tomography (MSOT), and near infrared (NIR) imaging of tumor-bearing BALB/c mice revealed that the intravenous injection of either L. lactis expressing β-galactosidase (β-gal) or infrared fluorescent protein (IRFP713) results in the establishment of the recombinant bacteria within tumor hypoxic niches. Overall, our data suggest that L. lactis represents an alternative strategy to target and deliver therapeutic molecules into the tumor hypoxic microenvironment.
Highlights
Melanoma is the most aggressive form of skin cancer and, if disseminated through the dermis, has a poor prognosis and high mortality rate
We aimed to investigate whether L. lactis can target and localize within melanoma hypoxic niches
A375Conditions and A2058 and Melanoma metastatic derived MeWo cells wereSkin-derived treated with increasing concentrations of cobalt chloride
Summary
Melanoma is the most aggressive form of skin cancer and, if disseminated through the dermis, has a poor prognosis and high mortality rate. The tumor microenvironment is a highly heterogeneous and complex landscape where interactions between malignant and non-malignant cells play an important role in cancer development, spread, and Cancers 2020, 12, 438; doi:10.3390/cancers12020438 www.mdpi.com/journal/cancers. An important feature of the tumor microenvironment is hypoxia, this factor is associated with advanced stages of malignancy and negatively affects the response to treatment by making drug diffusion to tumor sites difficult [4,5,6]. The hypoxic tumor region has a pivotal role in the development of multidrug resistance to anticancer drugs; immune response suppression; increased metastasis; and increased risk of mortality, independently of prognostic factors such as grade, histology, nodal status and size of the tumor [10,11,12,13]
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