Mathematical modeling of PDGF-driven glioma reveals the dynamics of immune cells infiltrating into tumors
| Autor: | Sarah Holte, Jianjun Paul Tian, Frank Szulzewsky, Xianyi Zeng, Eric C. Holland, Ben Niu, Tuan Anh Phan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Original article IDH1 Mutant wtIDH1 Infiltration dynamics Biology 1 wtIDH1 wild-type IDH1 CCL2 chemokine (C-C motif) ligand 2 a small cytokine that belongs to the CC chemokine family C5 complement component 5 a protein is encoded by the C5 gene lcsh:RC254-282 PDGF platelet-derived growth factor 03 medical and health sciences Mice 0302 clinical medicine Immune system Lymphocytes Tumor-Infiltrating muIDH1 mutant IDH1 Glioma CD4 cluster of differentiation 4 CD4+ T helper cells are white blood cells in immune system medicine Animals Humans muIDH1 Platelet-Derived Growth Factor Immune cell CXCL2 chemokine (C-X-C motif) ligand 2 a small cytokine belonging to the CXC chemokine family Brain Neoplasms Chemotaxis CD8+ T cells are cytotoxic killer cells in immune system Models Theoretical medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tumor site Chemotactic gradient field Isocitrate Dehydrogenase 030104 developmental biology 030220 oncology & carcinogenesis CIMP CpG island methylator phenotype Mutation Cancer research biology.protein CpG 5′-C-phosphate-G-3′ cytosine and guanine separated by one phosphate group RCAS/tva replication-competent avian sarcoma-leukosis virus (RCAS) entering cell through receptor tumor virus a (tva) Infiltration (medical) Platelet-derived growth factor receptor IDH1 isocitrate dehydrogenase |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 9, Pp 323-332 (2020) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | Background: Tumor-infiltrated immune cells compose a significant component of many cancers. They have been observed to have contradictory impacts on tumors. Although the primary reasons for these observations remain elusive, it is important to understand how immune cells infiltrating into tumors is regulated. Recently our group conducted a series of experimental studies, which showed that muIDH1 gliomas have a significant global reduction of immune cells and suggested that the longer survival time of mice with CIMP gliomas may be due to the IDH mutation and its effect on reducing of the tumor-infiltrated immune cells. However, to comprehend how IDH1 mutants regulate infiltration of immune cells into gliomas and how they affect the aggressiveness of gliomas, it is necessary to integrate our experimental data into a dynamical system to acquire a much deeper understanding of subtle regulation of immune cell infiltration. Methods: The method is integration of mathematical modeling and experiments. According to mass conservation laws and assumption that immune cells migrate into the tumor site along a chemotactic gradient field, a mathematical model is formulated. Parameters are estimated from our experiments. Numerical methods are developed to solve the problem. Numerical predictions are compared with experimental results. Results: Our analysis shows that the net rate of increase of immune cells infiltrated into the tumor is approximately proportional to the 4/5 power of the chemoattractant production rate, and it is an increasing function of time while the percentage of immune cells infiltrated into the tumor is a decreasing function of time. Our model predicts that wtIDH1 mice will survive longer if the immune cells are blocked by reducing chemotactic coefficient. For more aggressive gliomas, our model shows that there is little difference in their survivals between wtIDH1 and muIDH1 tumors, and the percentage of immune cells infiltrated into the tumor is much lower. These predictions are verified by our experimental results. In addition, wtIDH1 and muIDH1 can be quantitatively distinguished by their chemoattractant production rates, and the chemotactic coefficient determines possibilities of immune cells migration along chemoattractant gradient fields. Conclusions: The chemoattractant gradient field produced by tumor cells may facilitate immune cells migration to the tumor cite. The chemoattractant production rate may be utilized to classify wtIDH1 and muIDH1 tumors. The dynamics of immune cells infiltrating into tumors is largely determined by tumor cell chemoattractant production rate and chemotactic coefficient. |
| Databáze: | OpenAIRE |
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