Immunohistochemical Analysis of Pancreatic Secretory Trypsin Inhibitor Expression in Pulmonary Adenocarcinoma: Its Possible Participation in Scar Formation of the Tumor Tissues

Higashiyama, Masahiko; Doi, Osamu; Kodama, Ken; Yokouchi, Hideoki; Tateishi, Ryuhei; Matsuura, Nariaki; Murata, Atsuo; Naohiro, Tomita; Monden, Takushi; Ogawa, Michio

doi:10.1159/000217779

Cited by 15 publications

(10 citation statements)

References 17 publications

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“…SPINK1 is also produced in cancers of the colon (15,16), lung (17,18), liver (19), breast (20), prostate (21), and pancreas (20,22). In colon cancer, Gouyer and colleagues (23) identified and characterized SPINK1 as a major proinvasive secreted factor from the conditioned medium of HT-29 5M21 human colon cancer cells, which express a spontaneous invasive phenotype.…”

Section: Introductionmentioning

confidence: 99%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression.Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.

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Section: Introductionmentioning

confidence: 99%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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“…Although scar cancers of the lung have been recognized for several decades, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] a direct mechanistic association between the scar itself and the tumor has not been documented. Because no direct evidence has been observed for a causal association between the presence of scar tissue and cancer, several relatively recent publications have refuted the concept that pulmonary scars can be causal in lung cancer.…”

mentioning

confidence: 99%

“…In spite of these limitations, in some reports there is evidence that the scar (and scarring process) predates the tumor, [6][7][8][9][10][11] in others it is impossible to tell, 12,13 and in others there is evidence that there was an active scarring process as a result of the tumor. 2,3,5,[14][15][16] The basic assumption behind any conclusions of no association between a pulmonary scar and its "associated" tumor [1][2][3][4][5] is that the scar itself cannot have directly caused the tumor. In one article, 4 the authors even ruled out tuberculosis as a contributing cause even though 10 of 49 cancer patients had tuberculosis that predated the cancer.…”

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confidence: 99%

Inflammation as Cause for Scar Cancers of the Lung

Ardies

2003

Integr Cancer Ther

111

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The molecular and cellular basis of inflammation has become a topic of great interest of late because of the association between mechanisms of inflammation and risk for cancer. Inflammatory-mediated events, such as the production of reactive oxygen species (ROS), the activation of growth factors (for wound repair), and the altering of signaltransduction processes to activate cell-proliferation (to replace necrotic/apoptotic tissue cells), events that also can occur independently of inflammation, are all considered to be components of risk for a variety of cancers. Using scar cancer of the lung as an example, mechanisms of inflammation associated with recurring infections with Mycobacterium tuberculosis are discussed in the context that they may, in fact, be the major or sole cause of a cancer. Production of ROS, prostaglandins, leukotrienes, and cytokines in pulmonary tissues is greatly enhanced due to a cell-mediated immune response against macrophages infected with M. tuberculosis. These responses lead to the extensive fibrosis associated with recurring infections, possibly leading to decreased clearance of lymph and lymph-associated particles from the infected region. They also will enhance rates of cell division by inhibiting synthesis of P21, leading to enhanced progression from G0 arrest to G1 phase, from G1 to S phase, and from G2 to M phase of the cell cycle. By increasing rates of oxidative DNA damage and inhibiting apoptosis by enhancing synthesis of BCL-2, mutagenesis of progeny cells is enhanced, and these effects coupled with enhanced angiogenesis stimulated by COX-2 products lead to an environment that is highly conducive to tumorigenesis. Based on the evidence, it appears that but for an inflammatory response to recurring infections, some cases of scar cancer would not exist. By making appropriate lifestyle and dietary changes, a variety of anti-inflammatory effects can be produced, which should attenuate inflammation-induced risk for cancer.

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“…Its role has been considered to be a specific inhibitor that prevents autoactivation of trypsinogen in the pancreas and pancreatic juice [41]. Later studies showed that PSTI was also expressed in some extrapancreatic normal tissues [39,4345] and in various cancers, including pancreatic [34], colorectal [35], gastric [36], lung [37], and hepatocellular [38] cancers. It was found that the serum concentration of immunoreactive PSTI is elevated after surgery, trauma and severe infection [45][46][47], suggesting that PSTI is an acute phase reactant.…”

Section: Controlmentioning

confidence: 99%

“…These phenomena imply that PSTI has other physiological and pathological roles in addition to the inactivation of trypsin. Several papers suggest that tumor-derived PSTI acts as autocrine or paracrine growth factor [46,[50][51][52][53][54], and is associated with the tumor growth of stromal proliferation of fibrous tissues [36,37], although it has been reported recently that the evaluation of tumor-derived PSTI as a paracrine or autocrine growth factor is not definite and needs confirmation [55]. The hPSTI mRNA expression in type II citrullinemia patients was equivalent to the level in hepatic cancer portions (Figs.…”

Section: Controlmentioning

confidence: 99%

Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

et al. 1995

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Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS is deficient specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there are no apparent abnormalities in the amount, translational activity, and nucleotide sequence of hepatic ASS mRNA. Recent results of homozygosity testing indicate that the primary defect of type II citrullinemia is not within the ASS gene locus. In this present work, to understand the pathogenesis and pathophysiology of type II citrullinemia, we have characterized the alterations of gene expression in the liver of type II patients using the recently developed mRNA differential display method. Some cDNA bands expressed differently in type 1I citrullinemia patients and control were selected, cloned, and sequenced. Nucleotide sequence analysis and homology searching revealed an interesting clone which has 99% homology with the human pancreatic secretory trypsin inhibitor (hPSTI). Northern blot and RT-PCR analyses showed that the expression of hPSTI mRNA increased significantly in the liver of all type II patients tested. Furthermore, the concentration of hPSTI protein was found to be higher in the liver of type II citrullinemia than in control. These results suggest that hPST! may be related to the primary defect of type II citrullinemia and may be useful as a diagnostic marker, although the detailed mechanism of the high expression of hPSTI mRNA in type 11 liver is not yet known.

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Immunohistochemical Analysis of Pancreatic Secretory Trypsin Inhibitor Expression in Pulmonary Adenocarcinoma: Its Possible Participation in Scar Formation of the Tumor Tissues

Cited by 15 publications

References 17 publications

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Inflammation as Cause for Scar Cancers of the Lung

Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

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