The cell sources of exosomes exhibiting differential effects are varied and predominantly originate from endothelial cells, endothelial cell progenitors, and inflammatory cells. Cell signaling events between endothelial cells, endothelial progenitors, and stromal cells is crucial for the establishment and maintenance of microvascular integrity and has been shown to involve exosomes. Our results suggest that among exosomal cell sources, endothelial cells, endothelial cell progenitors, and inflammatory cells were more abundantly represented in IH and likely constitute the major source of the differences in tumor cell properties delineated herein. Exosomes are also able to govern the function of remote cells by secreting their cargos and reaching cells distant from their site of origin, and in fact, exosomes play a major role in the circulation of miRNAs. Exosomes are involved in the genetic transfer of specific miRNAs that enhance the invasive potential of several breast cancer cell lines. Furthermore, the tumor cell microenvironment is influenced by a wide range of biological components that are expressed and released by the tumor during the development and progression of cancer to promote its growth and metastatic progression., Exosomes released by tumor cells can interact with target cells by a number of mechanisms including (1) direct stimulation of the target by surface-expressed ligands, (2) receptor transfer between the tumor cell and the target, (3) horizontal transfer of genetic information to the target, and (4) direct stimulation of the target cell by endocytically expressed surface receptors. Since increasing evidence indicates that the effect of exosomes on target cells is mainly dependent on their intravesicular miRNA expression, we explored the miRNA content in exosomes using unbiased miRNA array approaches and identified 11 differentially expressed miRNAs, which are likely a critical component of their different effects on various tumor cell functions. Regarding their tumor cell targets, several canonical pathways emerged, and included 5'-adenosine monophosphate-activated protein kinase, which plays a key role as a master regulator of cellular energy homeostasis. The kinase is activated in response to stresses that deplete cellular adenosine triphosphate supplies, such as low glucose levels, hypoxia, ischemia, and heat shock., In addition, Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. In addition, dysregulation of the Hippo pathway contributes to cancer development., We also, identified 25 IH– modified networks, with three of these networks being involved in cancer biology (e-Fig 2), as well as multiple transcription factors, lending further credence to the intricate role of circulating exosomes in tumor biology.