The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

Martínez-Bosch, Neus; Guerrero, Pedro Enrique; Moreno, Mireia; José, Anabel; Iglesias, Mar; Munné-Collado, Jessica; Anta, Héctor; Gibert, Joan; Orozco, Carlos; Vinaixa, Judith; Fillat, Cristina; Viñals, Francesc; Navarro, Pilar

doi:10.18632/oncotarget.10199

Cited by 10 publications

(6 citation statements)

References 64 publications

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“…Furthermore, the proliferation of cancer cells was greatest at invasion sites in treated livers. These results are consistent with the model of stroma acting as a barrier against drug delivery, but also as a restriction on cancer growth 25,27,28,[34][35][36] . Thus, sunitinib may have released cancer cells from stromal suppression to result in substantially smaller, but more aggressive metastatic tumours.…”

Section: Discussionsupporting

confidence: 89%

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: Discussionsupporting

confidence: 89%

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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“…KRAS is a gene that regulates cellular signalling cascades associated with cellular growth, proliferation, and survival. Mutations in KRAS are common in human ductal carcinoma [25] and confer failure of sunitinib treatment in transgenic mouse models and possibly explain decreased response in some people to sunitinib [26]. These mutations are rarely reported in human acinar cell carcinoma and have recently been shown not to be present in canine acinar cell pancreatic carcinoma [27].…”

Section: Discussionmentioning

confidence: 99%

Toceranib phosphate (Palladia) for the treatment of canine exocrine pancreatic adenocarcinoma

Musser

Johannes

2021

BMC Vet Res

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Background Canine pancreatic carcinoma is a rare, aggressive tumour that is often diagnosed late in the course of disease. Effective treatment strategies have been elusive, and overall survival time is short. In humans, treatment with tyrosine kinase inhibitors alone, or in combination with IV gemcitabine, have been moderately effective. As canine and human pancreatic carcinomas share many clinical aspects, strategies that mimic human treatment regimens may confer a better outcome in canine patients. The aim of this study was to assess the role of the veterinary tyrosine kinase inhibitor, toceranib phosphate, in the treatment of cytologically or histologically confirmed canine pancreatic carcinomas. Results Retrospectively, medical records of dogs with confirmed pancreatic carcinoma treated with toceranib were reviewed. Eight dogs were identified that fit the inclusion criteria. Toceranib was well-tolerated by all patients. Six were treated in the gross disease setting. Four had image-based evaluation of clinical benefit (complete response, partial response, or stable disease of > 10 weeks). Of those patients, 1 achieved a partial response, 2 stable disease, and 1 had progressive disease, for an overall clinical benefit rate of 75 %. An additional dog had clinically stable disease that was not confirmed via imaging. The toceranib-specific median overall survival time was 89.5 days (range: 14–506 days). Conclusions Although limited in patient number, this small study suggests that toceranib may have biologic activity in dogs with pancreatic carcinoma. Larger, prospective studies are needed to confirm these preliminary results and define the use of toceranib in the microscopic disease setting.

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“…Cell Proliferation Assay. For HPSCs proliferation assays, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide] (MTT) staining was performed as described (101). For tumor-stroma crosstalk and proliferation assays using rGal1 (105), cells were starved for 48 h and stimulated with conditioned medium from HPSCs or rGal1 for 24 h. Cell proliferation was measured by phospho-histone H3 (P-HisH3) staining (see Immunofluorescence above).…”

Section: Methodsmentioning

confidence: 99%

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Orozco

Martínez-Bosch

Guerrero

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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122

123

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Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a -driven mouse model of PDA ( ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

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The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

Cited by 10 publications

References 64 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

Toceranib phosphate (Palladia) for the treatment of canine exocrine pancreatic adenocarcinoma

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

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