4.1 Extrinsic Pathways Linking Chronic Pancreatiti...
Besides neoplastic cells，the pancreatic cancer mass is composed of a stroma constituting of fibroblasts，vessels and leukocytes.Inflammation is the primary insult causing the robust stroma reaction surrounding pancreatic cancer cells（Elinav et al.2013）.Significantly，inflammatory cells，especially those leukocytes，are the major players in initiating and sustaining the inflammation reaction.The leukocytes within tumor stroma，as well as those cytokines and growth factors derived from leukocytes，constitute the complex extrinsic pathways，which play a critical role in cellular transformation and tumorigenesis process（Hidalgo 2010）.(https://www.daowen.com)
Tumor associated macrophages（TAMs）are the principal leukocytes driving an amplification of the inflammatory response in the tumor milieu.TAMs belong to the myeloid cell lineage and derive from myeloid progenitor cells.These precursor cells are located in the bone marrow；upon maturation，monocytes are released into the bloodstream.At the recruitment by certain chemokines，e.g.，CCL2 and CCL5，TAMs accumulate in tumor stroma，where TAMs are educated to facilitate cancer progression.TAMs assists tumor cell malignant behavior in many ways by releasing cytokines，growth factors and matrixdegrading enzymes and many angiogenic factors（Colotta et al.2009）.Numerous molecular alterations are involved in“TAM-pancreatic cancer”connection.For examples，administration of agonist CD40 antibody will activate macrophages，which help macrophages infiltrate tumors，became tumoricidal，and facilitated the depletion of tumor stroma（Beatty et al.2011）.TAMs secrete MIP3a to increase migration ability of pancreatic cancer cells by binding to the transmembrane receptor CCR6（Campbell et al.2005）.TAMs could convey proangiogenetic effects to pancreatic cancer cells.Blocking angiopoietin-2（ANG2），a TIE2 ligand and angiogenic factor，could impede the upregulation of Tie2 in TAMs，and decrease tumor angiogenesis of pancreatic cancer（Mazzieri et al.2011）.Furthermore，TAMs could help maintain the cancer stem cells，which have been linked to chemoresistance，metastatic dissemination，and the induction of immune suppression（Mitchem et al.2013）.Blockage the connection between TAMs and cancer stem cells could eliminate the cancer stem cells，improve chemotherapeutic response，and generate promising therapeutic efficacy.Therefore，TAMs and the complex cytokines network greatly enhance the tumorigenesis of pancreatic cancer.Targeted treatment against TAM may be promising in future pancreatic cancer therapeutics.