ZIA SC 009172 (ZIA) | |||
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Title | Cellular Interactions with Thrombospondin | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Roberts, David | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,003,208 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Aging (30.0%) Cancer (100.0%) Metastasis (10.0%) Organ Transplantation Research (30.0%) |
Breast (10.0%) Heart (5.0%) Leukemia (20.0%) Melanoma (20.0%) Vascular Disease (5.0%) |
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Research Type | |||
Cancer Progression & Metastasis Localized Therapies - Discovery and Development |
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Abstract | |||
The challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues. The protection of cell viability observed with CD47 is mediated autonomously by activation of protective autophagy. We examined whether CD47 blockade also protects cancer cells from cytotoxic chemotherapy. To evaluate blockade of CD47 in combination with chemotherapy in vivo, we employed the 4T1 breast cancer model and examined tumor and cardiac tissue viability as well as autophagic flux. A high-throughput screen revealed that blockade of CD47 does not interfere with the cytotoxic activity of anthracyclines against 4T1 breast cancer cells. Targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an anti-tumor innate immune response. Moreover, systemic suppression of CD47 protected cardiac tissue viability and function in mice treated with doxorubicin. Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, the absence of CD47 in did not elicit a protective effect in cancer cells, but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells. We previously reported that CD47 is present on extracellular vesicles (EVs) released by T cells and regulates the physiological activities of such EVs on target immune and vascular cells. We have extended those findings in two new publications. The first examined whether CD47 defines a distinct class of EVs. EVs mediate the intercellular transfer of RNAs, which alter gene expression in target cells. EV heterogeneity has limited progress towards defining their physiological functions and utility as disease-specific biomarkers. CD63 and MHC1 are widely used as markers to purify EVs. CD47 is also present on EVs and alters their effects on target cells, suggesting that specific surface markers define functionally distinct EVs. This hypothesis was addressed by comparing Jurkat T cell EVs captured using CD47, CD63, and MHC1 antibodies. These EV subsets have similar sizes but divergent RNA contents. Apart from differences in numbers of nonannotated transcripts, CD63+, MHC1+, and CD47+ EVs have similar overall contents of most noncoding RNA classes, but the relative enrichment of specific RNAs differs. The enrichment of micro-RNAs is highly divergent, and some including miR320a are selectively concentrated in CD47+ EVs. Small nucleolar RNAs including SNORD116@ and SNHG10 are also selectively enriched in CD47+ EVs, whereas no small nuclear RNAs are enriched in CD47+ EVs. Conversely, MHC1+ EVs are selectively enriched in a subset of tRNAs including TRE-CTC and TRR-CCG. This heterogeneity in RNA composition suggests multiple sorting mechanisms that direct specific RNAs into subsets of EVs that express specific surface markers. The second study examined the role of CD47 on EVs released by breast cancer cells in their regulation of vascular cells in the tumor microenvironment and the effects of therapeutic CD47 antibody blockade. Tumor cells release EVs into the tumor microenvironment that may facilitate malignant progression and metastasis. Breast carcinoma EVs express high levels CD47, which is the target of several experimental therapeutic antibodies that are currently in clinical trials. We analyzed changes in gene expression and function in human umbilical vein endothelial cells (HUVEC) induced by trea |