Tumor-hosting organs differentially influence tumor growth and response to therapy
Al Hamhoom, Yahya Saeed Y
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Tumor microenvironment plays an essential role in tumor growth and drug resistance. Accumulated evidence during recent years suggest the existence of environmental heterogeneity among different organs. We hypothesized that solid tumors growing in different organs have different microenvironments and, therefore, tumors may exhibit different growth and sensitivities to anticancer therapy. In this project, we established a multi-organ tumor model using the hydrodynamic cell delivery method to seed identical tumor cells in different organs: lung, liver, and kidneys. The multi-organ tumor model allowed us to assess the contributions of the stroma of different organs to tumor growth and its response to antitumor therapies. Ultrastructural analysis with electron microscopy demonstrated different tumor cell-stroma interactions in different organs. In the lung, tumor cells proliferated intravascularly, causing expansion of the capillaries diameter and loss of the mesh-like structure formed by the alveoli. In the liver and kidneys, tumor cells proliferated extravascularly, as evidenced by hepatic cords disruption and renal tubules disorganization, respectively. Another evidence of extravascular tumor growth in the liver and kidneys is the vascular damage that resulted from tumor cell intravasation. Moreover, tumor growth rate analysis demonstrated that renal cell carcinoma tumors grew more rapidly in the kidneys, whereas tumor growth in the lung was the slowest. Additionally, tumors in different organs responded differentially to 5-fluorouracil and cytokine gene therapy. 5-fluorouracil significantly suppressed tumor growth in the lung and liver, while tumors in the kidneys were resistant to the treatment. IL-12 gene therapy resulted in whole-body tumor suppression and prolonged animal survival. IFN-β gene therapy was effective in suppressing tumor growth in the liver but not effective for those in the lung and kidneys. Our results suggested that cancer cells, once metastasized in different organs, have different growth patterns and respond differently to treatment. This project highlights the differential influences of the stroma of different organs on the tumor growth and the need to consider this when designing anticancer therapies. Our data also imply that an animal model with multi-organ tumor growth is critical for the development of a new strategy for cancer metastasis treatment.
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