What are the Benefits of a Vascularized Tumoroid?
Vascularization of tumoroids (“tumor-like organoids”) enables more accurate recapitulation of in vivo conditions for basic research and translational medicine, the development of anti-angiogenic drugs and functional drug testing on patient-derived tumoroids to determine optimal treatment strategies in personalized medicine.
The value of tumoroids in translational research and personalized medicine
Tumoroids are essentially “tumor-like organoids” that are typically prepared using cells from primary tumors harvested from patients and can therefore mimic the microenvironment of a specific tumor. Tumoroids are playing an increasingly important role in studying disease progression. They complement xenograft and genetically engineered transplant models that are more laborious to prepare and provide 3D in vitro models that can be studied under highly controllable conditions. Patient-derived tumoroids (PDT) are promising tools in personalized medicine to guide the treatment of individual patients through functional precision medicine assays.
The importance of vascularization and angiogenesis in cancer drug delivery and targeting
Angiogenesis involves the formation of new blood vessels from pre-existing blood vessels, while neovascularization is the process of de novo blood vessel formation. Both play key roles in cancer development, progression, metastasis, and treatment. For example, poor drug transport and delivery, which depend on both the microvessel network of the tumor microenvironment (TME) and the vascularization around the tumor, are major causes of failure in anti-cancer drug screens and resistance to treatment. Not only that, the process of angiogenesis during tumor progression is itself a target for drug development (1).
Cancer patients vary in their response to anti-angiogenic agents, which means that predictive biomarkers can be used to measure angiogenic potential, detect drug resistance and guide anti-angiogenic treatment. The effects of drugs or genetic manipulations on sprouting angiogenesis can be measured using the spheroid-based sprouting assay (2, 3).
Vascularization is important in functional drug testing on patient-derived tumoroids to determine optimal treatment strategies in personalized medicine.
Examples of the use of vascularized tumoroids in cancer research and personalized medicine
Including vascularization within and around patient-derived tumoroids enables in vivo conditions to be more accurately recapitulated and support the study of angiogenesis and anti-angiogenic drugs, for example:
Colorectal cancer
Patient-derived tumoroids from primary colorectal tumors or a metastasis can be co-cultured with vascular cells (4). These were used to measure angiogenic potential of tumoroids and quantify the sensitivity to antiangiogenic therapies by measuring the induction of tube formation. This approach showed a dose-dependent response to the pro-angiogenic factor vascular endothelial growth factor A (VEGF-A) that could be abolished by treatment with anti-angiogenic agents under investigation.
Breast cancer
The vasculature of breast cancer plays a key role in tumor development and metastatic spread and angiogenesis involves the cooperation of cancer cells, stromal cells, such as fibroblasts and endothelial cells, secreted factors, and the extracellular matrix (ECM). In vitro models are required that can recapitulate this complex environment to boost success in drug development and screening. One example that meets this need is a 3D hybrid system consisting of co-cultures of mammary epithelial cells, fibroblasts, and endothelial cells (5). This model system supports epithelial morphogenesis in organoids/tumoroids and endothelial tubulogenesis and can be used to investigate epithelial-stromal interactions and tumor angiogenesis in the search for more selective and effective anticancer therapies.
Glioblastoma (GBM)
One of the characteristics of GBM is rich microvasculature and there is a significant correlation between the degree of angiogenesis and prognosis. Accurately recreating this neoangiogenesis and the tumor microenvironment through personalized in vitro disease models would support the development of new anti-angiogenic treatments. This has stimulated the development of tumoroid models consisting of GBM and endothelial cell spheroids in a fibrin gel containing human dermal fibroblasts that mimic the dynamics of tumor angiogenesis (6).
Non-small cell lung cancer (NSCLC)
A method to generate vascularized PDT has been developed that quickly and accurately recapitulates a patient tumor (7). This can be done in a matter of days and opens the possibility of rapid functional drug screening to support “back-to-patient” personalized treatment within two to three weeks of receiving a biopsy from the patient.
Conclusions
Vascularization of organoids and tumoroids enables in vivo conditions to be recapitulated more accurately for basic research and translational medicine, including the development of anti-angiogenic drugs. Vascularization is also important in functional drug testing on patient-derived tumoroids to determine optimal treatment strategies in personalized medicine.
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References
[1] Seitlinger J, Nounsi A, Idoux-Gillet Y, Santos Pujol E, Lê H, Grandgirard E, Olland A, Lindner V, Zaupa C, Balloul JM, Quemeneur E, Massard G, Falcoz PE, Hua G, Benkirane-Jessel N. Vascularization of Patient-Derived Tumoroid from Non-Small-Cell Lung Cancer and Its Microenvironment. Biomedicines. 2022 May 10;10(5):1103. doi: 10.3390/biomedicines10051103. PMID: 35625840; PMCID: PMC9138465.