Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma

Espósito, Irene; Menicagli, Michele; Funel, Niccola; Bergmann, Frank; Boggi, Ugo; Mosca, Francesca; Bevilacqua, Generoso; Campani, Daniela

doi:10.1136/jcp.2003.014498

Cited by 222 publications

(181 citation statements)

References 44 publications

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“…In addition, FGF2, FGF7 and FGF10 are implicated as autocrine and paracrine mediators of tumor-stroma interactions in pancreatic ductal adenocarcinomas [93]. In these tumors, mast cells, macrophages, and tumor cells overexpress VEGF-A, VEGF-C, and FGF2 and this was highly correlated to intratumor microvessel density [94].…”

Section: The Role Of the Fgf/fgfr System In Tumor/stroma Cross-talkmentioning

confidence: 93%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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a b s t r a c tFibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

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Section: The Role Of the Fgf/fgfr System In Tumor/stroma Cross-talkmentioning

confidence: 93%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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“…More specifically, pancreatic adenocarcinoma and chronic pancreatitis express a substantial proportion of proteins in common (22,25,26), placing patients that suffer from chronic pancreatitis at risk to develop pancreatic cancer (27). Indeed, mononuclear cells as mediators of nonspecific immune responses are recruited to pancreatic cancer and result in an angiogenic phenotype of cancer cells (21). Apart from inflammation signaling, EFEMP1 expression is dependent on regulation by female sex steroids.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the regulation of EFEMP1 expression in cancer. Because the microarray analyses had revealed an up-regulation of several mediators of inflammation pathways in L3.6pl cells and inflammatory cells have been reported to be involved in the development and progression of pancreatic cancer (21,22), we became interested in whether there was a link between IFN-a as a potent inflammatory stimulus and EFEMP1 expression in tumor cells. Interestingly, IFN-a provoked a >4-fold increase of EFEMP1 expression, as shown by quantitative RT-PCR (Fig.…”

Section: Differential Expression Of Efemp1 In Fg and L36pl Cells In mentioning

confidence: 99%

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Seeliger¹,

Čamaj²,

Ischenko³

et al. 2009

Molecular Cancer Research

100

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The progression of pancreatic cancer is dependent on local tumor growth, angiogenesis, and metastasis. EFEMP1, a recently discovered member of the fibulin family, was characterized with regard to these key elements of pancreatic cancer progression. Differential gene expression was assessed by mRNA microarray hybridization in FG human pancreatic adenocarcinoma cells and L3.6pl cells, a highly metastatic variant of FG. In vivo orthotopic tumor growth of EFEMP1-transfected FG cells was examined in nude mice. To assess the angiogenic properties of EFEMP1, vascular endothelial growth factor (VEGF) production of tumor cells, endothelial cell proliferation and migration, and tumor microvessel density were analyzed in response to EFEMP1. Further, tumor cell apoptosis, cell cycle progression, and resistance to cytotoxic agents were quantitated by propidium iodide staining and flow cytometry. In microarray hybridization, EFEMP1 was shown to be significantly up-regulated in L3.6pl cells compared with FG cells. Concordantly, EFEMP1 transfection of FG cells stimulated orthotopic and metastatic tumor growth in vivo. EFEMP1 expression resulted in a stimulation of VEGF production by tumor cells and an increased number of CD31-positive microvessels. Endothelial cell proliferation and migration were not altered by EFEMP1, indicating an indirect angiogenic effect. Further, EFEMP1 expression decreased apoptosis and promoted cell cycle progression in response to serum starvation or exposure to gemcitabine, 5-fluorouracil, and irinotecan. EFEMP1 has protumorigenic effects on pancreatic cancer in vivo and in vitro mediated by VEGF-driven angiogenesis and antiapoptotic mechanisms. Hence, EFEMP1 is a promising candidate for assessing prognosis and individualizing therapy in a clinical tumor setting. (Mol Cancer Res 2009;7(2):189-98)

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“…[30][31][32][33][34] While numerous investigations have focused on tumor-stromal interactions at the site of primary invasion, few have addressed these interactions in relation to the primary versus secondary sites of growth. [35][36][37][38][39][40] Our preliminary data of the host response in matched primary and metastatic disease suggests that the host stromal response generated to an infiltrating carcinoma may relate, in part, to the primary versus secondary organ microenvironment. The concept of a tumor microenvironment has long been hypothesized and has a rich history of literature to match, 41,42 and we provide additional unbiased data in support of this concept.…”

Section: Discussionmentioning

confidence: 99%

Stromal responses to carcinomas of the pancreas: Juxtatumoral gene expression conforms to the infiltrating pattern and not the biologic subtype

Ricci¹,

Kern²,

Hruban³

et al. 2005

Cancer Biology & Therapy

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If there is a "science" of tumor-stromal interactions, there must be a set of biologic rules that are organ-site dependent. One way to explore this hypothesis would be to compare the patterns of gene expression of two biologically distinct neoplasms that arise within the same organ site. Using nonradioactive in situ hybridization, we evaluated the gene expression patterns of three genes previously shown to be robust markers of the juxtatumoral stroma within eight infiltrating ductal adenocarcinoma of the pancreas (ApoC1, ApoD and MMP11), and compared these patterns to those associated with seven infiltrating colloid and tubular carcinomas arising in association with intraductal papillary mucinous neoplasms (IPMNs), a histologically distinct form of primary carcinoma of the pancreas, two surgically resected samples of chronic pancreatitis and two surgically resected pancreatic cancer liver metastases. Robust juxtatumoral stromal expression was noted for all three markers within all eight conventional infiltrating ductal adenocarcinoma tissues, but not in samples of chronic pancreatitis. Among the carcinomas arising within an IPMN, expression for all three markers was also noted for five of seven infiltrating carcinomas analyzed. However, when labeling for these three markers was analyzed with respect to infiltrative growth pattern, positive labeling was only seen in areas of tubular (ductal-type) growth and not in areas of colloid carcinoma. This observation was further supported by two infiltrating carcinomas arising in an IPMN that showed both tubular and colloid growth patterns within the same neoplasm indicating the host stromal response observed may relate to infiltrative growth pattern rather than the biology of the primary tumor type. Moreover, these robust patterns within conventional infiltrating ductal adenocarcinomas were not retained within matched metastases to the liver, indicating the importance of the tumor microenvironment in the host stromal response. Juxtatumoral stroma was found to be composed of a least two cell types, tumor-infiltrating macrophages and fibroblasts, highlighting the complexity of tumor-stromal interactions within an infiltrating carcinoma. Since the juxtatumoral gene expression response is the strongest indication of direct communication between stroma and cancer cells, we provide evidence of a stereotypical response to infiltrative growth that might predominate in tumor-stromal interactions independent of cancer type, a finding with clinical implications for therapeutic modalities that target this response in human tumors.

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Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma

Cited by 222 publications

References 44 publications

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Stromal responses to carcinomas of the pancreas: Juxtatumoral gene expression conforms to the infiltrating pattern and not the biologic subtype

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