While CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), the current standard of care for non-Hodgkin lymphoma (NHL), kills tumor cells, the accumulation of tumor cell “debris” can stimulate inflammation and tumor growth. Thus, cytotoxic cancer therapies are a double-edged sword. Previous studies have shown that apoptotic debris stimulates tumor growth. We hypothesize that (1) CHOP-generated tumor cell debris can promote lymphoma progression via release of pro-inflammatory cytokines; (2) blocking phosphatidylserine (PS), which is presented on the surface of apoptotic cells, may inhibit debris-stimulated cancer progression. METHODS: Lymphoma EL4 debris was generated by treating tumor cells with CHOP chemotherapy. EL4 debris was isolated via Ficoll gradient and co-injected with living EL4 tumor cells into immunocompetent C57BL/6 mice. Macrophage-secreted cytokines were measured via array analysis. RESULTS: Flow cytometry confirmed CHOP chemotherapy generated apoptotic/necrotic debris. Vincristine-, mafosfamide-, and prednisolone-generated lymphoma EL4 debris stimulated tumor growth by over 100-fold in a dose-dependent manner. Debris alone did not induce tumors, even at 250 days post-injection. Doxorubicin-generated EL4 debris stimulated tumor growth at low dose (1x105), but inhibited growth at high dose (9x105). Systemic administration of doxorubicin-generated EL4 debris or blocking PS in the cell debris generated by doxorubicin using annexin V or an anti-PS neutralizing antibody inhibited doxorubicin-generated debris-stimulated tumor growth. Therapy-generated debris stimulated macrophage pro-inflammatory cytokine production. CONCLUSIONS: CHOP chemotherapy-generated debris regulates tumor growth via cytokine production. Thus, harnessing the anti-tumor activity of inhibitory debris or neutralizing PS on stimulatory debris may be a novel anti-cancer approach. / 2018-07-11T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/23697 |
| Date | 11 July 2017 |
| Creators | Fernandes, Djanira Patricia |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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