A Myc-activated microRNA cluster enhances tumor angiogenesis. Human adenocarcinomas often have mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. These mutations can promote angiogenesis by increasing vascular endothelial growth factor (VEGF) production. However, Kras-transformed mouse colonocytes lacking p53 formed poorly vascularized tumors, while those with additional Myc expression showed increased vascularization. VEGF levels were not affected by Myc, but neovascularization correlated with reduced expression of anti-angiogenic proteins like thrombospondin-1 (Tsp1) and connective tissue growth factor (CTGF). The miR-17-92 microRNA cluster, which is upregulated in colonocytes coexpressing K-Ras and c-Myc, is predicted to repress Tsp1 and CTGF. Knockdown of miR-17-92 with antisense oligonucleotides partially restored Tsp1 and CTGF expression, and overexpression of miR-17-92 reduced these proteins. Tumors from miR-17-92-transduced cells were larger and better perfused. These findings show that microRNAs play a role in non-cell-autonomous Myc-induced tumor phenotypes. Myc promotes angiogenesis by upregulating VEGF and downregulating Tsp1. In genetically complex tumors, Myc and Ras cooperate to enhance angiogenesis. Myc overexpression in Ras-transformed cells led to increased tumor size and neovascularization. Tsp1 and CTGF levels were downregulated, and miR-17-92 was found to regulate these proteins. miR-17-92 overexpression reduced Tsp1 and CTGF levels, leading to increased tumor vascularization. miR-17-92 is activated by Myc and contributes to tumor growth. miR-17-92 overexpression in Ras cells led to larger, better-perfused tumors. These results suggest that miR-17-92 is a key regulator of Myc-induced angiogenesis. The study highlights the role of microRNAs in non-cell-autonomous tumor growth and angiogenesis.A Myc-activated microRNA cluster enhances tumor angiogenesis. Human adenocarcinomas often have mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. These mutations can promote angiogenesis by increasing vascular endothelial growth factor (VEGF) production. However, Kras-transformed mouse colonocytes lacking p53 formed poorly vascularized tumors, while those with additional Myc expression showed increased vascularization. VEGF levels were not affected by Myc, but neovascularization correlated with reduced expression of anti-angiogenic proteins like thrombospondin-1 (Tsp1) and connective tissue growth factor (CTGF). The miR-17-92 microRNA cluster, which is upregulated in colonocytes coexpressing K-Ras and c-Myc, is predicted to repress Tsp1 and CTGF. Knockdown of miR-17-92 with antisense oligonucleotides partially restored Tsp1 and CTGF expression, and overexpression of miR-17-92 reduced these proteins. Tumors from miR-17-92-transduced cells were larger and better perfused. These findings show that microRNAs play a role in non-cell-autonomous Myc-induced tumor phenotypes. Myc promotes angiogenesis by upregulating VEGF and downregulating Tsp1. In genetically complex tumors, Myc and Ras cooperate to enhance angiogenesis. Myc overexpression in Ras-transformed cells led to increased tumor size and neovascularization. Tsp1 and CTGF levels were downregulated, and miR-17-92 was found to regulate these proteins. miR-17-92 overexpression reduced Tsp1 and CTGF levels, leading to increased tumor vascularization. miR-17-92 is activated by Myc and contributes to tumor growth. miR-17-92 overexpression in Ras cells led to larger, better-perfused tumors. These results suggest that miR-17-92 is a key regulator of Myc-induced angiogenesis. The study highlights the role of microRNAs in non-cell-autonomous tumor growth and angiogenesis.