Table 2 Roles and mechanisms of the stromal cells in TME of pancreatic cancer

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. Pancreatic cancer cells-induced expression of miR-21 in CAF promotes the clonogenicity and pancreatoshpere formation [119, 120]

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. Pancreatic cancer potentially recruits protumoral TAMs by GM-CSF and then TAMs maintain the PCSCs by IL-6/STAT3 signaling pathway [132, 133]

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]

–

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]

1. PSCs induce apoptosis and anergy of T cells via galectin-1 [149, 150]

2. PSCs induce MDSCs via IL-6/JAK/STAT3 signaling axis [151, 152]

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]