Surprising role for fibrosis

Leake, Isobel

doi:10.1038/nrgastro.2014.97

Cited by 9 publications

(8 citation statements)

References 2 publications

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“…Despite the known protumorigenic properties of CAF, recent studies have suggested that depletion of fibrotic stroma has the potential to accelerate the disease and lead to cancer progression. 8 , 9 , 10 To assess how CAPaSC depletion by ProAgio affects the differentiation and aggressiveness of PDAC tumors, we analyzed tumor tissue from GEM-KPC mice at the end of the survival experiment. In concert with longer survival, tumors from ProAgio-treated GEM-KPC mice were more differentiated and had a decreased pathologic disease progression compared with vehicle-treated mice ( Figure 10 A and B ).…”

Section: Resultsmentioning

confidence: 99%

“…We asked why targeting fibrotic stroma by ProAgio did not result in more poorly differentiated and aggressive tumor as observed by other strategies that target fibrotic stroma. 8 , 9 , 10 The important difference is that ProAgio induces apoptosis via targeting integrin α v β 3 . In PDAC, only CAPaSC are integrin α v β 3 positive, while inactivated PaSC are α v β 3 negative.…”

Section: Resultsmentioning

confidence: 99%

“…However, recent studies of Shh and α-SMA gene deletion in PDAC GEM models suggest that some fibrotic stroma in PDAC may constitute a barrier that prevents metastatic spread of the tumor. 8 , 9 , 10 Depletion of fibrotic stroma results in increased metastasis and shorter survival in preclinical models and some early phase clinical studies. 8 , 9 , 11 These studies caused a very important controversy, “target or not-target fibrotic stroma in cancer therapies, particularly in treatment of PDAC?” 12 It should be noted that Shh or α-SMA gene deletion leads to global deletion of fibroblasts, resulting in downstream effects in excess of what would be expected from a tumor-targeted therapeutic.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment

Turaga

Sharma

Mishra

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin α v β 3 at a novel site and induces apoptosis in integrin α v β 3 -expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin α v β 3 , we aimed to analyze the effects of ProAgio in PDAC tumor. Methods Expression of integrin α v β 3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (Kras G12D ; p53 R172H ; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. Results ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse–KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. Conclusions Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment

Turaga

Sharma

Mishra

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…Gas6 also stimulates the proliferation of cardiac fibroblasts [41]. Since fibrosis and collagen deposition have been suggested to re-strain the metastatic spreading of pancreatic cancer cells [42–45], we next investigated whether Gas6 blockade could affect collagen deposition in pancreatic tumors. Pancreatic tumor tissues from control and anti-Gas6 treated mice were stained with picrosirius red to assess collagen deposition.…”

Section: Resultsmentioning

confidence: 99%

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

Mielgo

Ireland

Luckett

et al. 2019

Preprint

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Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits 2 pancreatic cancer metastasis. 3 Running title 4Gas6 blockade prevents pancreatic cancer metastasis 5 6 Growth arrest-specific gene 6 (Gas6) is a multifunctional factor that regulates several 50 processes in normal physiology and pathophysiology [1].Gas6 binds to the Tyro3, 51 Axl and Mer (TAM) family of receptor tyrosine kinases (TAM receptors) with the 52 highest affinity for Axl [2]. Gas6 supports erythropoiesis, platelet aggregation, 53 angiogenesis, efferocytosis, and inhibits the immune response [3]. Gas6 is critical for 54 the maintenance of immune homeostasis and mice deficient in Gas6 or TAM 55 receptors experience severe autoimmune diseases [4]. Gas6 and its main receptor 56 Axl are overexpressed in several cancer types including, breast, ovarian, gastric, 57 glioblastoma, lung and pancreatic cancer and their expression correlates with a poor 58 prognosis [5]. Axl is ubiquitously expressed in all tissues [6] but is particularly notable 59 in cancer cells, macrophages, dendritic cells and natural killer cells for its role in 60 driving immunosuppression and tumor progression [7-9]. Several cancer studies 61 have focused on the role of Gas6-Axl signaling on the tumor cells and have 62 demonstrated that Axl activation supports tumor cells proliferation, epithelial-63 mesenchymal transition (EMT), drug resistance, migration and metastasis [5]. 64 Factors secreted within the tumor microenvironment are able to sustain Gas6/Axl 65 signaling. Hypoxia Inducible Factor (HIF) has been shown to bind to the Axl 66 promoter region and upregulate its expression on renal cell carcinoma cells [10]. 67 Secretion of IL-10 and M-CSF by tumor cells induces tumor associated 68 macrophages to secrete Gas6 [11].69However, only a few studies have investigated the role of Gas6-Axl signaling in the 70 immune response to breast cancer, ovarian cancer and melanoma [7, 9]. 71 4In solid tumors such as breast or pancreatic cancer, the tumor stroma can represent 72 up to 80% of the tumor mass and actively influences cancer progression, metastasis 73 [12][13][14] and resistance to therapies [15][16][17]. 74 Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers 75 worldwide and better therapies are urgently needed [18]. Metastasis, therapy 76 resistance, and immunosuppression are key characteristics of pancreatic tumors [19, 77 20]. The Gas6-Axl pathway is activated in 70% of pancreatic cancer patients [21] 78 and is associated with a poor prognosis and increased frequency of distant 79 metastasis [22]. Blocking Gas6 or its receptor Axl inhibits cancer progression [23, 24] 80 and several Axl inhibitors are currently being tested in cancer patients, including 81 PDA patients. While the cancer cell autonomous functions of Gas6 are well 82 documented, the effect of Gas6 signaling in the stroma/immune compartment in 83 pancreatic cancer has not been fully explored. In these studies, we sought to 84 understand the effect of Gas6 bloc...

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“…1) [52,53]. Whether this stroma drives the progression of PDAC or acts as a defense [54][55][56], still remains controversial. It has been shown that high stromal activity, as assessed by α-smooth muscle actin (α-SMA) expression, is associated with a poor prognosis in patients with PDAC [57].…”

Section: Discussionmentioning

confidence: 99%

Computer-aided assessment of the extra-cellular matrix during pancreatic carcinogenesis: a pilot study

Grizzi

Fiorino²,

Qehajaj

et al. 2019

J Transl Med

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Background: A hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial. Our aim was to introduce a computer-aided method to precisely quantify the amount of pancreatic collagenic extra-cellular matrix, its spatial distribution pattern, and the degradation process. Methods: A series of normal, inflammatory and neoplastic pancreatic ductal adenocarcinoma formalin-fixed and paraffin-embedded Sirius red stained sections were automatically digitized and analyzed using a computer-aided method. Results: We found a progressive increase of pancreatic collagenic extra-cellular matrix from normal to the inflammatory and pancreatic ductal adenocarcinoma. The two-dimensional fractal dimension showed a significant difference in the collagenic extra-cellular matrix spatial complexity between normal versus inflammatory and pancreatic ductal adenocarcinoma. A significant difference when comparing the number of cycles necessary to degrade the pancreatic collagenic extra-cellular matrix in normal versus inflammatory and pancreatic ductal adenocarcinoma was also found. The difference between inflammatory and pancreatic ductal adenocarcinoma was also significant. Furthermore, the mean velocity of collagenic extra-cellular matrix degradation was found to be faster in inflammatory and pancreatic ductal adenocarcinoma than in normal. Conclusion: These findings demonstrate that inflammatory and pancreatic ductal adenocarcinomas are characterized by an increased amount of pancreatic collagenic extra-cellular matrix and by changes in their spatial complexity and degradation. Our study defines new features about the pancreatic collagenic extra-cellular matrix, and represents a basis for further investigations into the clinical behavior of pancreatic ductal adenocarcinoma and the development of therapeutic strategies.

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Surprising role for fibrosis

Cited by 9 publications

References 2 publications

Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment

Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

Computer-aided assessment of the extra-cellular matrix during pancreatic carcinogenesis: a pilot study

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