Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression

Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Cancer cell (Impact Factor: 23.52). 04/2011; 19(4):441-55. DOI: 10.1016/j.ccr.2011.03.002
Source: PubMed

ABSTRACT Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.

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Available from: Kenneth Boucher, Sep 27, 2015
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    • "Diagnoses of PDAC cases were confirmed by histological evaluation and consisted of a range of stages (10 stage IA or IB, 20 stage IIA, 47 stage IIB, 30 stage III, and 52 stage IV). Diagnostic and prognostic characteristics for CA 19-9 [2], haptoglobin [6], osteopontin[17], serum amyloid A [6], and TIMP-1 [17] in our cohort have been previously published, as have prognostic characteristics for MMP-7 [18]. Biomarker characterization for AXL, hyaluronic acid, and MMP-11 will be published elsewhere. "
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    ABSTRACT: Background Early detection screening of asymptomatic populations for low prevalence cancers requires a highly specific test in order to limit the cost and anxiety produced by falsely positive identifications. Most solid cancers are a heterogeneous collection of diseases as they develop from various combinations of genetic lesions and epigenetic modifications. Therefore, it is unlikely that a single test will discriminate all cases of any particular cancer type. We propose a novel, intuitive biomarker panel design that accommodates disease heterogeneity by allowing for diverse biomarker selection that increases diagnostic accuracy. Methods Using characteristics of nine pancreatic ductal adenocarcinoma (PDAC) biomarkers measured in human sera, we modeled the behavior of biomarker panels consisting of a sum of indicator variables representing a subset of biomarkers within a larger biomarker data set. We then chose a cutoff for the sum to force specificity to be high and delineated the number of biomarkers required for adequate sensitivity of PDAC in our panel design. Results The model shows that a panel consisting of 40 non-correlated biomarkers characterized individually by 32% sensitivity at 95% specificity would require any 7 biomarkers to be above their respective thresholds and would result in a panel specificity and sensitivity of 99% each. Conclusions A highly accurate blood-based diagnostic panel can be developed from a reasonable number of individual serum biomarkers that are relatively weak classifiers when used singly. A panel constructed as described is advantageous in that a high level of specificity can be forced, accomplishing a prerequisite for screening asymptomatic populations for low-prevalence cancers.
    Theoretical Biology and Medical Modelling 08/2014; 11(1):34. DOI:10.1186/1742-4682-11-34 · 0.95 Impact Factor
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    • "However, in cases of chronic injury or deregulated oncogenic Kras activity, this ductal progenitor-like state can be stabilized [15]. Chronic pancreatitis is a potent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC) in humans [15]–[18], and several mouse models have demonstrated injury and inflammation as permissive environments that accelerate the initiation and progression of PDAC development [11], [19]–[22]. Overall, inflammation appears to impact the rate-limiting step in acinar cell transformation, which is the ability to assume a de-differentiated state [15]. How de-differentiation can turn an acinar cell into another pancreatic cell (such as a pancreatic β-cell), or a cell with cancerous potential (as in cases of deregulated Kras activity) is of great interest. "
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    ABSTRACT: Normal tissue architecture is disrupted following injury, as resident tissue cells become damaged and immune cells are recruited to the site of injury. While injury and inflammation are critical to tissue remodeling, the inability to resolve this response can lead to the destructive complications of chronic inflammation. In the pancreas, acinar cells of the exocrine compartment respond to injury by transiently adopting characteristics of progenitor cells present during embryonic development. This process of de-differentiation creates a window where a mature and stable cell gains flexibility and is potentially permissive to changes in cellular fate. How de-differentiation can turn an acinar cell into another cell type (such as a pancreatic β-cell), or a cell with cancerous potential (as in cases of deregulated Kras activity) is of interest to both the regenerative medicine and cancer communities. While it is known that inflammation and acinar de-differentiation increase following pancreatic injury, it remains unclear which immune cells are involved in this process. We used a combination of genetically modified mice, immunological blockade and cellular characterization to identify the immune cells that impact pancreatic regeneration in an in vivo model of pancreatitis. We identified the innate inflammatory response of macrophages and neutrophils as regulators of pancreatic regeneration. Under normal conditions, mild innate inflammation prompts a transient de-differentiation of acinar cells that readily dissipates to allow normal regeneration. However, non-resolving inflammation developed when elevated pancreatic levels of neutrophils producing interferon-γ increased iNOS levels and the pro-inflammatory response of macrophages. Pancreatic injury improved following in vivo macrophage depletion, iNOS inhibition as well as suppression of iNOS levels in macrophages via interferon-γ blockade, supporting the impairment in regeneration and the development of chronic inflammation arises from aberrant activation of the innate inflammatory response. Collectively these studies identify targetable inflammatory factors that can be used to influence the development of non-resolving inflammation and pancreatic regeneration following injury.
    PLoS ONE 07/2014; 9(7):e102125. DOI:10.1371/journal.pone.0102125 · 3.23 Impact Factor
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    • "This abolished the increase in the number of invasive AGS cells stimulated with IL-22 (Figure 3B), and similar findings were also obtained for MKN28 cells (Figure 3C). Moreover, we examined whether IL-22 upregulates the expression of MMP7 and MMP13, which are likely to promote cell invasion in the downstream of IL- 22 signalling (Howlett et al, 2005; Fukuda et al, 2011). As shown in Figure 3D, IL-22 stimulation enhanced the expression of MMP7 and MMP13 in MKN28 and AGS cells, respectively. "
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    ABSTRACT: Background: Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion. Methods: Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay. Results: Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs. Conclusions: Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.
    British Journal of Cancer 06/2014; 111(4). DOI:10.1038/bjc.2014.336 · 4.84 Impact Factor
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