Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia

Abstract

Proliferating cancer cells secrete a multitude of factors impacting metabolism, interorgan communication, and tumor progression. The distribution of tumor-derived factors to distant organs occurs via the circulation, which provides an extensive reactive surface lined by endothelial cells. Primary tumor-derived proteins impact cancer progression by modulating endothelial cell activation at the (pre-)metastatic niche, which affects tumor cell dissemination as well as the outgrowth of seeded metastatic cells into overt tumors. In addition, new insight indicates that endothelial cell signaling contributes to metabolic symptoms of cancer, including cancer-associated cachexia, opening a new field of vascular metabolism research. This review addresses how tumor-derived factors systemically affect endothelial cell signaling and activation and impact distant organs as well as tumor progression.

Keywords: angiocrine signaling; cachexia; metastasis; systemic signaling; vascular endothelium.

FIGURE 1.

Primary tumor-derived factors systemically affect the distant vasculature to regulate metastasis, thrombosis, and cachexia Primary tumor-derived factors change endothelial cell signaling at the pre-metastatic niche to promote tumor cell dissemination and modulate angiogenesis in metastatic nodules, which affects tumor colonization. Additionally, tumor-derived factors may cause changes in organ function of cancer patients and induce thrombosis in the distant vasculature. During cachexia, cancer cells may regulate endothelial cell signaling to induce adipocyte wasting by activating lipolysis and browning. In skeletal muscle, tumor-derived factors may cause proteolysis and impaired regeneration via abnormal angiocrine signaling. Image was created with BioRender.com, with permission.

FIGURE 2.

Primary tumor-derived factors affect tumor cell dissemination and colonization at distant sites A: graphical illustration of the effects of primary tumor-derived factors on endothelial cells (ECs) at the premetastatic niche. VEGF, TNF-α, transforming growth factor β (TGF-β), and placental growth factor (PlGF) act directly on ECs at the pre-metastatic niche and thereby induce EC hyperpermeability and enhance tumor cell dissemination. Granulocyte-colony stimulating factor (G-CSF) affects transmigration indirectly via expanding Ly6G⁺Ly6C⁺ granulocytes, which activate ECs by secreting Bv8. B: Schematic representation of the effects of primary tumor-derived factors on ECs at the metastatic site. VEGF, PlGF, TGF-β, and PDGF-BB are secreted by tumor-educated platelets and induce angiogenesis thereby promoting tumor colonization. VEGFR2⁺ bone marrow-derived cells (BMCs) are enhanced and contribute to these processes. Cancer-associated fibroblasts (CAFs) from the primary tumor secrete growth differentiation factor 15 (GDF15) and thrombospondin-1 (TSP-1), which enhance or reduce angiogenesis at the metastatic site, respectively. Molecules such as angiostatin, nANGPTL4, and endostatin are secreted by the primary tumor and directly act on ECs to reduce sprouting and thereby inhibit the outgrowth of metastatic nodules. Tumor-derived factors promoting cancer cell dissemination or colonization are depicted in green and tumor-derived factors inhibiting these processes are highlighted in red. Image was created with BioRender.com, with permission.

FIGURE 3.

Endothelial cell signaling pathways during cancer-associated cachexia A: tumor inflammation as well as tumor-derived IL-6 induce endothelial cell (EC) activation and the expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Endothelial-derived IL-6 may trigger trans-signaling in adipose tissue causing browning and lipolysis as well as IL-6 release, which in turn activates classical signaling in muscle leading to muscle wasting via mitophagy. Activated skeletal muscle secretes soluble IL-6Rα, which is necessary for trans-signaling in endothelial cells and adipocytes. B: tumor-derived lipocalin-2 (Lcn2) and inflammatory factors may induce Lcn2 signaling in ECs via the 24p3R receptor increasing vascular integrity and decreasing permeability. However, EC activation can also induce Lcn2 expression in ECs, which may cause satellite cell activation and muscle regeneration, insulin resistance, and brown adipose tissue (BAT) activation as well as reduced appetite and food intake. Additionally, Lcn2 induces VEGF release from tumor cells which promotes (tumor) angiogenesis. C: VEGF from cancer cells and myofibers as well as other inflammatory stimuli induces Dll-4 expression and release from ECs. Dll-4-Notch signaling in satellite cells supports their self-renewal and quiescence. In myotubes, Dll-4 signaling causes muscle wasting and disruptions of the sarcomere structure. Image was created with BioRender.com, with permission.