Invasion and migration are important for pancreatic cancer metastasis, especially hematological dissemination. Once pancreatic cancer cells invade capillaries in the tumor tissue, they can enter portal veins for distal metastasis, such as metastasis to the liver and lung. The pancreatic cancer microenvironment can facilitate metastasis by promoting pancreatic cancer cells invasion and migration. For instance, TAMs promote invasion by secreting matrix proteins and proteases to alter the ECM composition. Macrophage inflammatory protein-3α (MIP-3α) derived from TAMs in human pancreatic cancer tissue is considered a regulator of pancreatic cancer cell invasion [
131]. MIP-3α can bind to CCR6 on pancreatic cells to upregulate their MMP9 expression, which increases pancreatic cancer cells invasion in collagen IV [
132,
133]. Cancer-associated fibroblasts (CAFs) express high levels of palladin, an actin-associated protein, which promotes pancreatic cancer cells invasion by remodeling the ECM by regulating the activity of the small GTPase Cdc42 [
134]. Among these cells in the microenvironment, PSCs play a more important role in tumor invasion and migration. In vitro studies have shown that CD10
+ PSCs can promote the invasiveness of SUIT-2 pancreatic cancer cell lines in a murine cotransplantation model [
117], and collagen-I, produced by PSCs, is the major mediator of PSC-induced haptokinesis of Panc1 and haptotaxis of UlaPaCa by activating FAK signaling via binding to integrin α2β1 [
135]. Hypoxia plays a critical role in pancreatic cancer progression by inducing HIF1 to activate numerous genes involved in invasion and metastasis, such as NF-κB [
136], MMP-2 [
137,
138], quiescin-sulfhydryl-oxidase-1 (QSOX1) [
139], CX3CR1 [
140], and lysyl-oxidase (LOX) [
141]. Clinical specimens have shown that SHH, induced by hypoxia via a ligand-independent mechanism [
142], is overexpressed in pancreatic cancer cells and activates PSCs to secrete high levels of perineural invasion-associated molecules to promote perineural invasion in pancreatic cancer [
143]. Galectin-1, which has been discussed previously, is expressed by PSCs and can induce PSC secretion of SDF-1 by NF-κB signaling and increase the migration and invasion of pancreatic cancer cells [
144]. HGF, secreted by PSCs, can bind to c-Met on the surface of pancreatic cancer cells to promote their invasion and migration via the HGF/c-Met/survivin pathway [
145], which is negatively regulated by the p53/p21 pathway, and HGF inhibition by AMG102 antibody can reduce pancreatic cancer metastasis dramatically in an orthotopic model of pancreatic cancer and the pancreatic cancer cell line AsPC-1 [
146]. Periostin, which is a 90-kD secretory protein that was originally identified as an osteoblast-specific factor, is aberrantly upregulated in PSCs [
147]. Abnormally high expression levels of periostin can increase α-SMA, periostin, collagen-1, fibronectin and TGFβ expression in PSCs and can promote growth, resistance to starvation, and invasion of pancreatic cancer cells [
147]. Further studies have demonstrated that periostin creates the tumor-supportive microenvironment by binding to EGFR to trigger the Akt and Erk pathway [
148].