Tumor microenvironment is considered nowadays as one of the main players in cancer development and progression. Tumor microenvironment is highly complex and consist of non-tumor cells (i.e. cancer-associated fibroblast, endothelial cells or infiltrating leucocytes) and a large list of extracellular matrix proteins and soluble factors. The way in that microenvironment components interact among them and with the tumor cells themselves is very complex and only partially understood. However, it is now clear that these interactions govern and modulate many of the cancer hallmarks such as cell proliferation, the resistance to death, the differentiation state of tumor cells, their ability to migrate and metastasize and the immune response against tumor cells. One of the microenvironment components that has emerged in the last years with strength is a heterogeneous group of multifaceted proteins grouped under the name of matricellular proteins. Matricellular proteins are a family of non-structural matrix proteins that regulate a variety of biological processes in normal and pathological situations. Many components of this family such as periostin (POSTN), osteopontin (SPP1) or the CNN family of proteins have been shown to regulate key aspect of tumor biology, including proliferation, invasion, matrix remodeling and dissemination to pre-metastatic niches in other organs. Matricellular proteins can be produced by tumor cells itself or by other tumor-associated cells, and their synthesis can be affected by intrinsic and/or extrinsic tumor cell factors. In this review, we will focus on the role of periostin in the development and progression of cancer. We will describe their functions in normal tissues and the mechanisms involved in their regulation. We will analyze the tumors in which their expression is altered and their usefulness as a biomarker of tumor progression. Finally, we will speculate about future directions for research and therapeutic approaches targeting periostin.

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1^low cells present a migratory and invasive phenotype, while EWSR1::FLI1^high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1^low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.