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Formation xlstat1/9/2024 There is evidence that the endothelium can impact cancer progression by either preventing or supporting tumor growth and metastasis formation. Recent research, however, suggests that ECs of blood vessels play a role in cancer progression that is far beyond delivering oxygen and nutrients. ![]() In this context, many studies have been focusing on identifying the role of tumor-associated macrophages and cancer-associated fibroblasts in cancer progression. Co-evolution of cancer cells and tumor stroma can lead to the generation of niches that support tumor growth, both at the primary site and at distant metastatic sites. The interaction between cancer cells and cells of the microenvironment is a crucial determinant of cancer progression. ![]() The tumor microenvironment is composed of a plethora of different cell types and ECM. In addition to its role in normal development, recent studies provide evidence that proliferation and migration of cancer cells is also largely dependent on interactions with the surrounding stroma. For example, the ability of breast epithelial cells to form TDLU-like structures in a 3-dimensional environment in vitro is strongly enhanced by the presence of breast ECs. Multiple studies have shown that the stromal compartment plays a fundamental role when it comes to epithelial morphogenesis. Formation of TDLU is highly dependent on heterotypic interactions between the epithelial cells and the surrounding vascular-rich stroma. Ducts and TDLUs are surrounded by a basement membrane, embedded in stroma consisting of extracellular matrix (ECM) as well as multiple cell types including fibroblasts, immune cells, and endothelial cells (ECs) forming the microvessels. In breast morphogenesis, the epithelial compartment generates branching ducts that result in terminal duct lobular units (TDLU). ![]() Organ morphogenesis is dependent on heterotypic interactions between multiple cell types. Targeting this interaction may provide a novel possibility to improve cancer treatment. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. ![]() To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. tumorigenic breast epithelial cell lines and primary ECs. Here, we sought out to analyze epithelial–endothelial cross talk in the breast using isogenic non-tumorigenic vs. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. The tumor microenvironment is increasingly recognized as key player in cancer progression.
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