Breast tumor progression is a complex process involving intricate crosstalk between the primary tumor and its microenvironment. In the context of breast tumor‐lymphatic interactions, it is unclear how breast cancer cells alter the gene expression of lymphatic endothelial cells and how these transcriptional changes potentiate lymphatic dysfunction. Thus, there is a need for in vitro lymphatic vessel models to study these interactions. In this work, a tumor‐lymphatic microfluidic model is developed to study the differential conditioning of lymphatic vessels by estrogen receptor‐positive (i.e., MCF7) and triple‐negative (i.e., MDA‐MB‐231) breast cancer cells. The model consists of a lymphatic endothelial vessel cultured adjacently to either MCF7 or MDA‐MB‐231 cells. Quantitative transcriptional analysis reveals expression changes in genes related to vessel growth, permeability, metabolism, hypoxia, and apoptosis in lymphatic endothelial cells cocultured with breast cancer cells. Interestingly, these changes are different in the MCF7‐lymphatic cocultures as compared to the 231‐lymphatic cocultures. Importantly, these changes in gene expression correlate to functional responses, such as endothelial barrier dysfunction. These results collectively demonstrate the utility of this model for studying breast tumor‐lymphatic crosstalk for multiple breast cancer subtypes.
This content will become publicly available on May 3, 2025
Cancer nanomedicines predominately rely on transport processes controlled by tumor‐associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor‐associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer‐associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super‐resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor‐associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport‐related genes, especially motor protein genes, in tumor‐associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer‐associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor‐associated endothelial cell‐mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines.
more » « less- Award ID(s):
- 2048130
- NSF-PAR ID:
- 10516991
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Advanced Materials
- ISSN:
- 0935-9648
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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