Background
The advances of chemotherapy in pancreatic cancer, since 2000
Interactions and mechanisms between stromal cells and pancreatic cancer cells in TME
PSCs
Proliferation | Migration | ECM production | |
---|---|---|---|
Hedgehog | + | ||
JAK-STAT | + | ||
MAPK | + | + | + |
PI3K | + | + | + |
PKC | + | ||
Rho kinase | + | ||
Smads | + | ||
Wnt/β-catenin | + | + | |
PPAPγ | + | ||
TF(AP-1, NK-κB, Gli-1) | + | + | + |
CAFs
TAMs
MDSCs
Maintenance of PCSCs | Modeling of ECM | Proliferation and survival | Migration | |
---|---|---|---|---|
PSCs | 1. PSCs secreted-IL-6 stimulates STAT3 to enhance colony formation and progression of PanIN [102] 2. PSCs enhance the CSCs phenotype of cancer cells by TGF-β [103] 3. PSCs promote sphere formation by paracrine Nodal/Activin signaling [104] 4. PSCs enhance the spheroid-forming of cancer cells and induces the expression of CSC related genes ABCG2, Nestin and LIN28 [105] | 1. Hypoxic PSCs exhibit highly organized parallel patterned matrix fibers to promote cancer cell motility by inducing directional migration via PLOD2 [106] 2. PSC-derived collagen I induces haptokinesis and haptotaxis of cancer cells by activating FAK signaling via binding to integrin α2β1 [107] 3. PSCs promote invasion of cancer cells by secretion of MMP3 [108] 4. TGF-β inhibits the secretion of lumican in PSCs, which could enhance PSCs adhesion and mobility [109] 5. PSCs modulate 3D collagen alignment to promote the migration of cancer cells [110] | 1. PSCs induce cancer cell proliferation via galectin-1 [111] 2. PSCs improve the survival of cancer cell by supporting the metabolism through autophagic alanine secretion [112] 3. PSCs promote the proliferation of cancer cells via β1-integrin [113] 4. PSCs promote the proliferation of cancer cells by secreting kindlin-2 [114] 5. Autophagic PSCs produce ECM molecules and IL6 to promote the proliferation and invasion of cancer cells [115] | 1. PSCs promote the migration of cancer cells via EMT process [116] 2. PSCs promote the migration and invasion of cancer cells via Stromal Cell-Derived Factor-1/CXCR4 Axis [117] 3. PSCs can stimulate the proliferation, migration and chemokine (C-X-C motif) ligands 1 and 2 in pancreatic cancer cells by secreting exosome [118] |
CAFs | 1. CAFs can secrete components of the ECM and change the structure of the ECM via MMPs and β1-integrin [121] 2. FAP expressing fibroblasts remodel the ECM to enhance directionality and velocity of pancreatic cancer cells by beta1-integrin/FAK signal pathway [122] 3. CAF-secreted SPARC maintain the vascular basement membrane to inhibit the metastasis of pancreatic cancer cells [123] | 1. FAP expressing fibroblasts inactivate retinoblastoma (Rb) protein in pancreatic cancer cells to promote the proliferation [124] 2. Pancreatic cancer cell induced-SOCS1 gene methylation in CAF activates STAT3 and IGF-1 expression to support growth of pancreatic cancer [125] 3. CAF-drived CXCL12 promotes proliferation of cancer cells by binding CXCR4 [126] 4. Gemcitabine treatment can increase release the exosome of CAF to promote proliferations of cancer cells through Snail [127] | 1. CAFs stimulate the migration of PDAC cells through paracrine IGF1/IGF1R signaling [128] 2. CAFs promote migration of pancreatic cancer cells by secreting extracellular vesicles, ANXA6/LRP1/TSP1 [129] 3. CAFs promote the migration and EMT of pancreatic cancer cells via IL-6 [130] 4. Pancreactic cancer cell-induced low expression of CD146 in CAF promoted migration and invasion of cancer cells [131] | |
TAMs | 1. Cancer cell derived-CCL2 induced by HIF-1 recruits TAMs to activate PSC to remodel the ECM [134] 2. TAMs secrete granulin to activate hepatic stellate cells, resulting in a fibrotic environment to promote liver metastasis of pancreatic cancer [135] 3. The interactions of TAMs and PSCs contribute the fibrogenesis during pancreatic cancerogenesis [136] | 1. TAMs induced-upregulation of CDA improves the survival of cancer cells when treated by gemcitabine [137] 2. Pancreatic cancer cells can secret lectin Reg3 beta to promote M2 through STAT3 singnal pathway and then M2 can inhibit apoptosis and prolong the viability of cancer cells [138] | 1. TAMs secrete glial-derived neurotrophic factor, inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) to promote migration of cancr cells [139] 2. Soluble factors from cancer cells trigger scavenger receptor A on TAMs to promote migration of cancer cells [140] 3. Cancer cell over expressed heparanase induce procancerous phenotype of macrophage to promote migration of cancer cells via IL6/STAT3 signal pathway [141] | |
MDSCs | 1. Pancreatic cancer can induce MDSCs by STAT3 signal pathway and MDSCs increase the ALDH(+)PCSCs [142] | – | 1. Pancreatic cancer cells can induce MDSCs that promote tumor cell survival and accumulation [143] | – |
EMT | Angiogenesis | Immunosuppression | |
---|---|---|---|
PSCs | 1. PSCs decrease the expression of E-carderin and ZO-1, increase the expression of β-catenin and vimentin in pancreatic cancer cells [116, 144] 2. IL-6 from PSCs promote EMT in PDAC cells via Stat3/Nrf2 pathway [145] | 1. PSCs accompany cancer cells to metastatic sites, stimulate angiogenesis, and are able to intravasate/extravasate to and from blood vessels [146] 2. Heptocyte growth factor (HGF)/c-Met pathway plays a role in PSC-induced tube formation of endothelial cells formation of human microvascular endothelial cells [147] 3. PSCs express both pro- and anti-angiogenic factors to maintain the balance of angiogenesis [148] | 3. PSCs can sequester CD8+ T cells by interaction between CXCL12 and CXCR4 [153] 4. PSCs activate mast cells to produce IL13 and tryptase, stimulating proliferation of both cancer cells and PSCs [154] |
CAFs | 1. CAF-drived CXCL12-CXCR4 signal promotes pancreatic cancer cell EMT and invasion by activating the P38 pathway [155] 2. CAFs promote EMT of pancreatic cancer cells via IL-6/PI-3 signal pathway [156] | 1. CAFs potentially induce angiogenesis by CXCL12/CXCR4 axis and SPARC [157] | 1. CAFs induce immunosuppressive environment to dampen the effects of antibodies against CTLA-4 and PD-L1 by CXCL12 [12] 2. CAFs weaken the function and survival of T cells by arginase II [158] 3. CAFs induce apoptosis of T cells by galectin-1 [159] 4. CAFs can induce M2 by secreting M-CSF to promote the pancreatic tumor cell growth, migration, and invasion [160] |
TAMs | 1. M2-polarized TAMs promote EMT in pancreatic cancer cells, partially via TLR4/IL-10 signaling pathway [161] 2. Both M1 and M2-polarized TAM decrease expression of E-cadherin and increase expression of vimentin [162] | 1. TAMs potentially induce angiogenesis by secreting VEGF to promote metastasis of pancreatic cancer [163] | 1. Blockage of CSFR reprograms TAM s to an antigen-presenting phenotype and improves antitumor T cell responses [164] 2. TAMs potentially induce Treg to promote metastasis of pancreatic cancer [163] 3. Radiation induced M-CSF in cancer cells recruits TAMs to construct a immunosuppressive environment to hamper antitumor response [165] 4. Ly6C(low)F4/80(+) macrophages outside of the tumor microenvironment regulate infiltration of T cells into tumor tissue and establish a site of immune privilege [166] |
MDSCs | – | – | 1. The MDSCs in pretumroal and pancreatic cancer tissue have high arginase activity and suppress T-cell responses [167] 2. Pancreatic cancer induces bone marrow mobilization of MDSCs to promote tumor growth by suppressing CD8(+) T cells [168] 3. PAUF enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway [169] 4. Pancreatic cancer dampens SHIP-1 to expand MDSCs and enhance the immunosuppressive functions [170] 5. Depletion of Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity against pancreatic cancer [143] |