Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma. Chen Gang,Nakamura Ikuo,Dhanasekaran Renumathy,Iguchi Eriko,Tolosa Ezequiel J,Romecin Paola A,Vera Renzo E,Almada Luciana L,Miamen Alexander G,Chaiteerakij Roongruedee,Zhou Mengtao,Asiedu Michael K,Moser Catherine D,Han Shaoshan,Hu Chunling,Banini Bubu A,Oseini Abdul M,Chen Yichun,Fang Yong,Yang Dongye,Shaleh Hassan M,Wang Shaoqing,Wu Dehai,Song Tao,Lee Ju-Seog,Thorgeirsson Snorri S,Chevet Eric,Shah Vijay H,Fernandez-Zapico Martin E,Roberts Lewis R Cancer research Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632-45. ©2016 AACR. 10.1158/0008-5472.CAN-15-2556

Alpha2beta1 integrin in cancer development and chemoresistance. Naci Dalila,Vuori Kristiina,Aoudjit Fawzi Seminars in cancer biology Extracellular matrix, via its receptors the integrins, has emerged as a crucial factor in cancer development. The α2β1 integrin is a major collagen receptor that is widely expressed and known to promote cell migration and control tissue homeostasis. Growing evidence suggests that it can be a key pathway in cancer. Recent studies have shown that α2β1 integrin is a regulator of cancer metastasis either by promoting or inhibiting the dissemination process of cancer cells. The α2β1 integrin signaling can also enhance tumor angiogenesis. Emerging evidence supports a role for α2β1 integrin in cancer chemoresistance especially in hematological malignancies originating from the T cell lineage. In addition, α2β1 integrin has been associated with cancer stem cells. In this review, we will discuss the complex role of α2β1 integrin in these processes. Collagen is a major matrix protein of the tumor microenvironment and thus, understanding how α2β1 integrin regulates cancer pathogenesis is likely to lead to new therapeutic approaches and agents for cancer treatment. 10.1016/j.semcancer.2015.08.004

TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment. Molecular therapy : the journal of the American Society of Gene Therapy Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment. 10.1016/j.ymthe.2021.01.002

Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Zeltz Cédric,Primac Irina,Erusappan Pugazendhi,Alam Jahedul,Noel Agnes,Gullberg Donald Seminars in cancer biology The tumor microenvironment (TME) is a complex meshwork of extracellular matrix (ECM) macromolecules filled with a collection of cells including cancer-associated fibroblasts (CAFs), blood vessel associated smooth muscle cells, pericytes, endothelial cells, mesenchymal stem cells and a variety of immune cells. In tumors the homeostasis governing ECM synthesis and turnover is disturbed resulting in abnormal blood vessel formation and excessive fibrillar collagen accumulations of varying stiffness and organization. The disturbed ECM homeostasis opens up for new types of paracrine, cell-cell and cell-ECM interactions with large consequences for tumor growth, angiogenesis, metastasis, immune suppression and resistance to treatments. As a main producer of ECM and paracrine signals the CAF is a central cell type in these events. Whereas the paracrine signaling has been extensively studied in the context of tumor-stroma interactions, the nature of the numerous integrin-mediated cell-ECM interactions occurring in the TME remains understudied. In this review we will discuss and dissect the role of known and potential CAF interactions in the TME, during both tumorigenesis and chemoresistance-induced events, with a special focus on the "interaction landscape" in desmoplastic breast, lung and pancreatic cancers. As an example of the multifaceted mode of action of the stromal collagen receptor integrin α11β1, we will summarize our current understanding on the role of this CAF-expressed integrin in these three tumor types. 10.1016/j.semcancer.2019.08.004