Mechanism of pathological angiogenesis in adipose tissue and tumor

Angiogenesis is critical for both malignant diseases, such as cancer, and non-malignant diseases, such as obesity and metabolic disorders. Majority of tissues and organs are highly vascularized. The malfunctions of tissue microenvironment are always accompanied with or dependent on the alterations of vasculature. Therefore, anti-angiogenic agents provide novel therapeutic targets for prevention and treatment of malignant and non-malignant diseases.

This thesis presents the identification and further investigation of mechanism of angiogenesis in adipose tissue metabolism and cancer development. Multiple factors spatiotemporally regulate adipogenesis and angiogenesis. In a transgenic mouse model described in the first constituent paper, FOXC2 in the adipose tissue affects angiogenesis, vascular patterning and functions. FOXC2 controls angiopoietin-2 (Ang-2) expression by direct activation of its promoter in adipocytes. Remarkably, an Ang-2 specific antagonist L1-10 reverses the vascular alterations.

In another physiological model described in the second paper, exposure of mice to cold temperature leads to activation of angiogenesis in both white and brown adipose tissues. Proangiogenic factors, such as VEGF, are upregulated, and endogenous angiogenesis inhibitors, such as thrombospondin, are downregulated during the adipose tissue transformation. Intriguingly, the cold-induced angiogenesis is independent of hypoxia. VEGFR2 blockage abolishes the cold-induced angiogenesis and significantly impairs nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage results in the opposite effects. Therefore, the application of angiogenesis modulators can have conceptual implications for the treatment of obesity and disorders.

In the third paper, we show both in vitro and in vivo that PDGF-B markedly induces erythropoietin (EPO) mRNA and protein expression levels by targeting the PDGFR positive stromal compartment. Tumor-produced PDGF-B systemically affects spleen and liver by causing hepato-splenomegaly and extramedullary hematopoiesis. PDGF-B induces erythropoietin and promotes tumor growth by, 1) stimulating tumor angiogenesis and 2) stimulating extramedullary hematopoiesis leading to increased oxygen perfusion. Thus, the EPO signaling pathway may be crucial for the development of anti-PDGF cancer therapy.

List of scientific papers

I. Xue Y, Cao R, Nilsson D, Chen S, Westergren R, Hedlund EM, Martijn C, Rondahl L, Krauli P, Walum E, Enerbäck S, Cao Y (2008). FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue. Proc Natl Acad Sci USA. 105(29): 10167-72. Epub 2008 Jul 11
https://pubmed.ncbi.nlm.nih.gov/18621714

II. Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S, Feldmann HM, Liang Z, Zhu Z, Nedergaard J, Cannon B, Cao Y (2009). Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 9(1): 99-109
https://pubmed.ncbi.nlm.nih.gov/19117550

III. Wang Z, Xue Y, Jensen L, Lim S, Ye X, Hedlund EM, Zhu Z, Cao R, Galter D, Cao Y (2009). PDGF-B modulates hematopoiesis and tumor angiogenesis by switching on hypoxia-independent erythropoietin production in stromal cells. [Manuscript]