In hepatocellular

In hepatocellular this website carcinoma cells, stiffer matrices were found to promote proliferation and chemoresistance, while cells surviving after chemotherapy on softer matrices exhibited a reversible dormant phenotype associated with expression of CSC markers [148]. Finally, increased matrix stiffness favors TGFβ-induced EMT over apoptosis [149]. Thus a picture emerges in which enhanced matrix stiffness maintains or endows CSCs properties on tumor cells, can regulate dormancy, and determines the response to EMT-inducing factors. A remarkable finding that has emerged from the study of the formation of pre-metastatic niches is the long-range

signaling that allows primary tumors to establish metastatic niche structures. Factors such as VEGF-A and PlGF produced by primary tumors act distantly on the bone marrow to mobilize VEGFR1+ BMDC that contribute to pre-metastatic niche mTOR inhibitor cancer formation [122]. Similarly, primary tumor-derived VEGF-A, TNFα and TGFβ induce expression of S100A8 and S100A9 in developing pre-metastatic niches, which in turn recruits CD11b+ myeloid cells [123]. Recent studies have implicated primary tumor-derived microvesicles

and exosomes in the long-range signaling involved in pre-metastatic niche formation [150]. Microvesicles and exosomes contain membrane and cytoplasmic proteins, as well as nucleic acids derived from the cell of origin. They can be transported via the blood, and the cargo they carry can interact with target cells and modify their behavior [151]. Exosomes released

from rat pancreatic adenocarcinoma cells together with CD44v6 in the soluble fraction complement each other in generating a niche for efficient tumor outgrowth [152]. Microvesicles released from CD105-positive renal carcinoma CSCs stimulate angiogenesis, upregulate VEGF-A, MMP2 and MMP9 expression in pre-metastatic sites in the lung, and promote lung metastasis [153]. Microvesicles have also been shown to be involved in the bilateral communication between tumor cells and fibroblasts, with tumor-derived microvesicles acting to upregulate MMP9 expression in fibroblasts [154]. The requirement before for long-range signals derived from primary tumors that orchestrate the formation of pre-metastatic niches may account for the association between elevated risk of metastasis development and increasing primary tumor size. It would seem reasonable to assume that the tumor-derived growth factors and other signaling molecules involved would need to rise above a given systemic concentration threshold before having an effect in the bone marrow or potential sites of pre-metastatic niches. Larger tumors would be expected to produce more of the requisite signaling molecules, and therefore the concentration of these molecules in the circulatory system should also rise concomitantly.

Leave a Reply

Your email address will not be published. Required fields are marked *

*

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>