Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes

Abstract

The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo. Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation. Ductal adenocarcinoma of the pancreas (PDAC) is an aggressive cancer with slim chances of survival 1-3. Once metastasized, chemotherapy provides the main treatment option but standard regimes offer minimal survival extension 4-6. PDAC's chemo-resistance may involve the characteristic desmoplastic stroma that comprises most of the tumour tissue 7-11. The stroma contains a population of carcinoma-associated fibroblasts (CAFs) that can differentiate from pancreatic stellate cells, among other sources 12,13. CAFs surround cancer cells and provide structural and signalling functions 9,13-21. Thus, the mechanisms that activate stromal fibroblasts during cancer progression have potential as therapeutic targets 12,13,22-24. CAFs are a target for novel PDAC therapies, but there is controversy over their role in tumour progression 13. On one hand, stromal depletion from PDAC-like tumours using Hedgehog (Hh) pathway inhibitors can stimulate angiogenesis and enhance drug delivery 25. On the other, stromal myofibroblast depletion can suppress angiogenesis and enhance tumour progression 26-28. Together, these studies imply that the stroma can have both a protective role for the tumour 28 but also restrict its progression 27,29. Importantly, the balance between these roles may depend on sub-populations of different fibroblast types in the microenvironment 22,30. Clearly, improved treatment requires a better understanding of the stroma and its fibroblastic populations. However, even less is known about cancer-fibroblast interactions during metastasis, despite the largely stromatic composition of metastatic tissue 7-11,22,23,31,32. Metastasis-associated fibroblasts (M...

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

“…These chemokines like CXCL8 and CXCL12 collaboratively aggravate invasion and angiogenesis in pancreatic cancer, via their corresponding receptors, CXCR2 and CXCR4 ( Matsuo et al, 2009 ). Meanwhile, these signals could also drive macrophages to M2 polarization ( Pausch et al, 2020 ; Zhang et al, 2020 ). Moreover, TAM-induced inflammation also promotes EMT in PDAC, which is defined as a phenotypic switch from epithelial to mesenchymal phenotype cell through gradually vanishing cell polarity and intercellular connections, consequently enhancing tumor cell migration and invasion.…”

Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma

“…CAFs secrete VEGF, angiopoietin-1, and hepatocyte growth factor (HGF), which increase the proliferation rate of endothelial cells and subsequently support angiogenesis [ 6 , 85 , 86 ]. Furthermore, co-culture of fibroblasts with metastatic pancreatic cancer cells stimulates the proliferation of fibroblasts and promotes secretion of the proangiogenic proteins CXCL8 and C-C motif ligand 2 (CCL2) [ 87 ]. On the other hand, CAFs express vasohibin-1, as well as stimulate pancreatic cancer cells to produce endostatin, both of which act as antiangiogenic factors [ 85 , 88 , 89 ].…”

Is the C-C Motif Ligand 2–C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?

“…Pancreatic ductal adenocarcinoma cells educate fibroblasts through the secretion of CCL2 and IL-8, leading to CAFs and similar metastasis-related fibroblasts. CAFs and metastasis-related fibroblasts promoted angiogenesis and tumor progression by interacting with cancer cells [60]. Moreover, CCL2 involves tumor cell extravasation through the endothelium.…”