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Tumor engineering: orthotopic cancer models in mice using cell-loaded, injectable, cross-linked hyaluronan-derived
Yanchun Liu1, Xiao Zheng Shu, Glenn D Prestwich
1Center for Therapeutic Biomaterials and Department of Medicinal Chemistry, The University of Utah, Salt Lake City 84108-1257, USA.
Abstract:
Current cancer xenograft models used to evaluate new anticancer therapies are limited to "good take" cell lines, fail to mimic normal human disease, and poorly predict clinical outcomes. We now describe the use of an injectable, in situ cross-linkable synthetic extracellular matrix (sECM) to deliver and grow cancer cells in vivo. The hyaluronan (HA)-derived sECMs were seeded with breast, colon, and ovarian cancer cells prior to gelation, and then injected subcutaneously into mammary fat pads, subserosally in colons, and intracapsularly in ovaries, respectively. Two cell lines were used for each type of cancer, and results were compared with orthotopic injection of cells in serum-free medium. At 4 weeks postinjection, four parameters were measured: (i) incidence and size of cancer at the injection site, (ii) vascularization or necrosis of new cancer tissue, (iii) cancer seeding in adjacent tissues, and (iv) metastasis to lymph nodes and other vital organs. In addition, the activation of the phosphoinositide 3-kinase (PI 3-K) signaling pathway was analyzed immunohistochemically. Overall, orthotopic delivery of cancer cells in sECM hydrogels showed clear advantages: (i) increased incidence of cancer formation and reduced variability in tumor size, (ii) enhanced growth of organ-specific cancers with good tumor-tissue integration, (iii) improved vascularization and reduced necrosis within the tumor, (iv) reduced cancer seeding on adjacent tissues, and (v) better general health of animals. Thus, engineered tumors represent an improved approach to traditional tumor xenografts, and facilitate studies in cancer biology, invasion and metastasis, as well as the investigation of new therapeutic and diagnostic protocols.
Insights
Synthetic extracellular matrix (sECM) hydrogels improve cancer xenograft models by enhancing tumor formation, vascularization, and organ-specificity, offering a better approach for cancer research and therapy development.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Translational Oncology
Background:
- Current cancer xenograft models have limitations in mimicking human disease and predicting clinical outcomes.
- Existing models often rely on specific cell lines and lack physiological relevance.
Purpose of the Study:
- To develop and evaluate an injectable, in situ cross-linkable synthetic extracellular matrix (sECM) for improved cancer xenograft models.
- To compare the efficacy of sECM-based delivery with traditional orthotopic injection methods.
Main Methods:
- Hyaluronan (HA)-derived sECMs were seeded with breast, colon, and ovarian cancer cells.
- Cells in sECM were injected into orthotopic sites (mammary fat pads, colon, ovaries).
- Evaluated tumor incidence, size, vascularization, necrosis, local seeding, metastasis, and PI 3-K pathway activation.
Main Results:
- sECM hydrogels significantly increased cancer formation incidence and reduced tumor size variability.
- Enhanced organ-specific cancer growth with improved tumor-tissue integration and vascularization.
- Reduced necrosis, decreased cancer seeding in adjacent tissues, and improved animal health were observed.
Conclusions:
- Engineered tumors using sECM hydrogels represent a superior alternative to traditional xenografts.
- This improved model facilitates studies in cancer biology, invasion, metastasis, and therapeutic development.
- sECM hydrogels enhance the reliability and translational potential of preclinical cancer research.
