The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment

Lafaro, Kelly J.; Melstrom, Laleh G.

doi:10.1016/j.ajpath.2018.09.009

Cited by 64 publications

(55 citation statements)

References 111 publications

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“…Together our experiments elucidate therapeutically relevant interactions in the metastatic PDAC microenvironment 7,9,23,30,64 . Some therapeutic approaches consider manipulating the microenvironment's vasculature to either starve the tumour (by decreasing perfusion) or enhance drug delivery (by increasing perfusion) 7,9,65 .…”

Section: Discussionmentioning

confidence: 85%

“…The tumour microenvironment is a complex system of dynamic interdependencies. Fibroblasts and related cells are integral to PDAC's aggression and resistance, and are keys to building successful therapeutic combinations 7,9,12,13,[22][23][24]30,31,64 . Our experiments reveal that active metastatic fibroblasts may aid the formation and colonization of pancreatic cancer by promoting angiogenesis at the boundary of cancer cells and resisting anti-angiogenic compounds like sunitinib.…”

Section: Discussionmentioning

confidence: 99%

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

Pausch

Aue

Wirsik

et al. 2020

Sci Rep

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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...

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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

Pausch

Aue

Wirsik

et al. 2020

Sci Rep

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“…The study of the cellular interactions taking place between the cancer and stroma has recently emerged as an important topic in pancreatic cancer research [43][44][45]. Multiple new stromal targets of potential clinical importance in PDAC are currently being investigated [46].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

Amrutkar

Larsen

Aasrum

et al. 2020

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.

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“…Pancreatic cancers are composed of extracellular matrix and various cell types including transformed cancer cells, fibroblasts, endothelial cells, pericytes, macrophages, and a host of other immune cells. Activated CAFs are among the most abundant cell type, comprising between 15-85% of the stromal cells [24,25]. The definition of a cancer associated fibroblast (CAF) is not straight forward [19].…”

Section: Cafs and Tumor Stroma/extracellular Matrixmentioning

confidence: 99%

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Norton

Foster

Chinta

et al. 2020

Cancers

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Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

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The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment

Cited by 64 publications

References 111 publications

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

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

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

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