Abstract
BackgroundThe breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs). Emerging data indicate that TAFs increase production and signaling by TGF-β cytokines, while the role of TGF-β signaling in the regulation of tumor blood vessels is not fully understood. The current study presents evidence that TAFs enhance the organization of tumor blood capillaries, and TGF-β signaling plays an important role in this response.MethodsTumor vascularization was studied in xenograft models of breast carcinoma cells, alone and in combination with fibroblasts. TGF-β signaling in breast cancer cells was modulated by expression of kinase-inactive TGFBR1-K232R (dnTGFBR1) or constitutive-active TGFBR1-T204D (caTGFBR1) receptor mutants. The architecture of tumor blood capillaries was assessed by immune-histochemical analysis of endothelium and pericytes. The role of TGF-β-Smad signaling in fibronectin expression was examined using adenoviral transduction of signaling components.ResultsOur studies revealed that TAFs significantly increase the lumen size of blood microvessels. Inactivation of TGF-β signaling in tumor cells by dnTGFBR1 reduced the microvessel density and lumen sizes, decreasing tumor growth. In contrast, caTGFBR1-tumors exhibited greater vessel density and lumen sizes. Tumors with inactive dnTGFBR1 showed lower amounts of TAFs, while caTGFBR1 increased amounts of TAFs compared to the control. Inspection of pericytes and endothelial cells in tumor vasculature revealed that TAFs enhanced vessel coverage by pericytes, vascular cells supporting capillaries. This effect was impaired in dnTGFBR1-tumors, whereas active caTGFBR1 enhanced the association of pericytes with endothelium. Accordingly, dnTGFBR1-tumors exhibited the presence of hemorrhages, a sign of fragile blood vessels. Biochemical analysis showed that TGFBR1-SMAD signaling up-regulates fibronectin, a prominent regulator of endothelium-pericyte interactions.ConclusionsThe current study indicates that tumor-fibroblast crosstalk enhances tumor vascularization by increasing the pericyte-endothelium association via a mechanism involving the TGFβ-fibronectin axis. The tumor-fibroblast model represents a useful system for dissecting the complex interactions governing tumor angiogenesis and developing new approaches to therapeutic targeting tumor vasculature.
Highlights
The breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs)
The current study examined whether this tumor-fibroblast crosstalk is affected by disruption of transforming growth factor-β (TGF-β) signaling in tumor cells
To assess a TGF-β signaling mechanism, we examined the role of SMADs in Discussion This study revealed that tumor-associated fibroblasts (TAFs) enhance tumor vascularization and tumor TGF-β signaling contributes to this response
Summary
The breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs). Compelling evidence points to the tumor microenvironment (TME) as a major factor influencing breast cancer progression and response to therapy [2]. In the breast cancer TME, cancer and host stromal cells are engaged in complex and dynamic interactions that promote tumor angiogenesis and obstruct the anticancer immune response. TAFs have been implicated in recruitment of pro-angiogenic myeloid immune cells such as macrophages and myeloid-derived suppressor cells (MDSCs), thereby promoting tumor angiogenesis and metastasis [4, 5]. The roles of different cellular components of the TME and their interactions in tumor angiogenesis are not fully understood
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