Effects of taurolidine and octreotide on tumor growth and lipid peroxidation after staging-laparoscopy in ductal pancreatic cancer

Irrigation with taurolidine after laparoscopy decreases tumor growth in colon carcinoma. In pancreatic cancer subcutaneous therapy with octreotide decreases oxidative stress and carcinogenesis as well. However, it is still unclear, whether irrigation with taurolidine or octreotide after laparoscopic pancreatic biopsy reduces tumor growth in pancreatic cancer as well. In 60 Syrian hamsters ductal pancreatic adenocarcinoma was induced by weekly injection of 10mg/kg body weight N-nitrosobis-2-oxopropylamine s.c. for 10 weeks. In week 16 laparoscopic pancreatic biopsy by use of carbon dioxide was performed (gr. 1, n = 20) with subsequent laparoscopic irrigation with taurolidine (gr. 2, n = 20) or octreotide (gr. 3, n = 20). In week 25 hamsters were sacrificed. Our results show that macroscopic visible primary tumors were found in only one animal of the taurolidine group (5.9%), compared to 42.1% in the saline and 62.5% in the octreotide group (P<0.05). Carcinomas were smaller after saline (6+/-23 mm(2)) than after octreotide irrigation (70+/-120 mm(2), P<0.05). In conclusion this study showed that laparoscopic irrigation with taurolidine after pancreatic biopsy inhibited tumor growth in ductal pancreatic adenocarcinoma.     

Influence of conjugated vs. conventional linoleic acid on liver metastasis and hepatic lipidperoxidation in BOP-induced pancreatic cancer in Syrian hamster

While conjugated linoleic acid (CLA) is regarded as an essential fatty acid with anticarcinogenic effects, conventional linoleic acid (LA) is reported to promote tumour growth in various experimental studies probably caused by high sensitivity to non-enzymatic lipid peroxidation. In order to evaluate the impact of dietary LA and CLA on liver metastasis and lipidperoxidation (LPO), 60 Syrian hamsters were injected with 10 mg N -nitrosobis-2-oxopropylamine (BOP)/kg body weight s.c. for 12 weeks. Animals were fed a special diet containing LA or CLA. The experiment was terminated after 24 weeks. Incidence, number and size of liver metastases were histologically determined. Furthermore, the activities of antioxidative enzymes and concentration of hepatic lipidperoxidation were measured intra- and extrametastatically. Incidence, number and size of liver metastases did not differ between the tumour groups. Otherwise, antioxidative enzyme activity of GSH-Px was higher in non-metastatic liver, while SOD activity and lipidperoxidation were increased in liver metastases. Conclusively there was no difference between the groups fed with LA and CLA according to the impact on liver metastasis in ductal pancreatic cancer.     

Effects of selective COX-2 and 5-LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster

Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis, however, the effect on liver metastasis in pancreatic cancer is still unknown. Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N-nitrosobis-2-oxopropylamine (BOP) in Syrian hamster. Animals received selective inhibition of cyclooxygenase-2 (Celebrex) and 5-lipoxygenase (Zyflo). In week 33, hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined. Furthermore, size and number of liver metastases per animal were determined and concentration of PGF1alpha, PGE2 and leukotrienes was measured in hepatic and pancreatic tissue. Combined therapy (Celebrex+Zyflo) significantly decreased incidence, number and size of liver metastases. Furthermore extra- and intrametastatic concentration of PGE2 was reduced by this treatment in hepatic tissue. Single Cox-2-inhibition (Celebrex) decreased intrametastatic hepatic PGF1alpha and PGE2 concentration while PGF1alpha concentration was reduced in non-metastatic liver (nml). Moreover 5-LOX-inhibition (Zyflo) decreased intrametastatic PGE2 concentration as well as PGF1alpha and PGE2 in nml. In pancreatic carcinomas highest LT-concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour-free tissue. Hepatic LT-concentration was significantly lower in the control groups than in nml of the tumour groups. Combination of Cox-2-inhibition and 5-Lox-inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma.     

Influence of conjugated and conventional linoleic acid on tumor growth and lipid peroxidation in pancreatic adenocarcinoma in hamster

Conventional linoleic acid (LA) is regarded as a promotor of carcinogenesis. However, the effect of its conjugated derivative on cancer is still unknown. Therefore we investigated the influence of conventional and conjugated LA on tumor growth and lipid peroxidation in a solid model of pancreatic adenocarcinoma in Syrian hamsters. 60 male hamsters were randomized in 4 groups (Gr.) (n=15). Gr. 1 and 2 received 0.5 ml 0.9% sodium chloride subcutaneously (s.c.) once a week while Gr. 3 and 4 were injected 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly for 12 weeks to induce pancreatic cancer. Gr. 1 and 3 received a diet containing conventional LA, Gr. 2 and 4 were fed a diet of conjugated LA. After 29 weeks all animals were sacrificed, pancreas was weighed and examined macroscopically and histologically. The level of lipid peroxidation and activities of glutathion peroxidase and superoxide dismutase were determined in tumor-free as well as in pancreatic carcinoma tissue. Different diets did not influence the incidence of pancreatic carcinoma, however, pancreas weight was increased by conjugated LA compared to conventional LA. Furthermore both diets decreased the activity of glutathion peroxidase and increased the level of lipid peroxidation in pancreatic intratumoral tissue. The content of conjugated LA in dietary did not influence pancreatic tumor growth in a solid model of pancreatic adenocarcinoma in Syrian hamsters.     

Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: A potential role for MMP-9

Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37°C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity.Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 ± 4, LPS: 26 ± 6 mmHg*mL*min^–1). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro31-9790: 38 ± 3, doxycycline: 51 ± 3 mmHg*mL*min^–1), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock.     

Influence of octreotide and tamoxifen on tumor growth and liver metastasis in N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancer in Syrian hamsters

In prospective clinical trials single octreotide therapy or combined therapy with tamoxifen has improved the quality of life and survival time in patients with pancreatic cancer. In this study we analyzed the influence of octreotide and tamoxifen on tumor growth and liver metastases in chemically induced pancreatic adenocarcinoma in Syrian hamsters. Octreotide alone and the combined therapy (octreotide/tamoxifen) decreased the incidence of macroscopic pancreatic carcinomas as well as the number and size of liver metastases. The combined therapy showed no superior effect to octreotide alone. Furthermore, there was no difference between the tamoxifen and the control group.     

Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer—Is there a correlation to tumour growth and liver metastasis?

Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) (n=15). While Gr. 1-3 were healthy control groups, Gr. 4-6 weekly received subcutaneous injections of 10mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1-6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1alpha, PGE(2)) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4-6: 54.5% vs. 45.5% vs. 9.1%, P<0.05) as well as incidence of liver metastasis (Gr. 4-6: 90.9% vs. 72.7% vs. 36.4%, P<0.05). Furthermore concentration of PGF(1)(alpha), PGE(2) and LT were significantly increased in pancreatic carcinoma compared to tumour-free tissue. Moreover levels of PGF(1)(alpha) and PGE(2) were higher in liver metastasis than in extrametastatic hepatic tissue. However, in Gr. 6 (FISH-OIL) intrametastatic concentration of LT was significantly lower than in non-metastatic hepatic tissue as well as in Gr. 4 and Gr. 5. FISH-OIL decreased number of visible pancreatic tumours and incidence of histological proven liver metastasis. This effect might be caused by a decrease of intrametastatic concentration of LT compared to extrametastatic hepatic tissue.     

Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation

The objective of the current study was to assess the expression of matrix metalloproteinase 9 (MMP-9) in pancreatic ductal carcinoma and to examine its correlation with chosen clinico-anatomical parameters. The study group consisted of 36 patients with pancreatic ductal carcinoma. Tumors were stained using immunohistochemical method (NCL -MMP-9, Novocastra). No correlation was found between tumor MMP-9 expression and age, gender or grade of histological malignancy. However, statistical analysis revealed a relationship between tumor MMP-9 expression and histological type (adenocarcinoma mucinosum) of pancreatic carcinoma. The expression was strongly correlated with lymph node involvement and occurrence of distant metastases (p<0.00001). The results indicate a correlation between the expression of MMP-9 in pancreatic ductal carcinoma and worse prognosis (shown by lymph node involvement and distant metastases).     

Effect of matrix metalloproteinase inhibition on adipose tissue development

The effect of Ro 28-2653, a synthetic matrix metalloproteinase (MMP) inhibitor, on adipose tissue development was studied in mice kept on a high fat diet (HFD). Five-week-old male wild-type (C57Bl/6J) mice were fed the HFD (42% kcal as fat, 20.1 kJ/g) and received daily p.o. instillations of inhibitor (30 mg/kg) or vehicle. After 15 weeks of the HFD, the body weight gain was lower in the inhibitor-treated group (7.4 +/- 0.88 g versus 10 +/- 1.4 g) whereas the weights of the isolated subcutaneous (SC) or gonadal (GON) fat deposits were 10-15% lower. The number of adipocytes in adipose tissues of the inhibitor-treated mice was somewhat higher (10-17%) but their diameter was smaller (about 10%). In situ zymography showed reduced gelatinolytic activity in SC (about 2.7-fold) and GON (1.4-fold) adipose tissue of inhibitor-treated mice, whereas their fibrillar collagen content was higher (1.5- and 4.7-fold, respectively). In both SC and GON adipose tissues of inhibitor-treated mice, MMP-2 (gelatinase A) and MMP-14 (membrane type-1 MMP) were 2- to 3-fold upregulated, whereas MMP-9 (gelatinase B) mRNA levels were not affected. Thus, in this in vivo model partial inhibition of gelatinolytic activity is associated with moderate effects on adipose tissue development and cellularity. Possibly, enhanced MMP expression to some extent counteracts the in vivo effect of the inhibitor in adipose tissue.     

Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1

Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-Ras(G12D) that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellular signal-regulated kinase (ERK) 1/2 and proinvasive matrix metalloproteinases (MMP), indicators of poor prognosis. However, the distinct molecular mechanisms necessary for K-Ras/ERK1/2 signaling and its influence on MMP-directed stromal invasion in primary human pancreatic ductal epithelial cells (PDEC) have yet to be elucidated in three-dimensions. Expression of oncogenic K-Ras(G12D) alone in genetically defined PDECs reveals increased invadopodia and epithelial-to-mesenchymal transition markers, but only when cultured in a three-dimensional model incorporating a basement membrane analog. Activation of ERK2, but not ERK1, also occurs only in K-Ras(G12D)-mutated PDECs cultured in three-dimensions and is a necessary intracellular signaling event for invasion based upon pharmacologic and short hairpin RNA (shRNA) inhibition. Increased active invasion of K-Ras(G12D) PDECs through the basement membrane model is associated with a specific microarray gene expression signature and induction of MMP endopeptidases. Specifically, MMP-1 RNA, its secreted protein, and its proteolytic cleavage activity are amplified in K-Ras(G12D) PDECs when assayed by real-time quantitative PCR, ELISA, and fluorescence resonance energy transfer (FRET). Importantly, shRNA silencing of MMP-1 mimics ERK2 inhibition and disrupts active, vertical PDEC invasion. ERK2 isoform and MMP-1 targeting are shown to be viable strategies to attenuate invasion of K-Ras(G12D)-mutated human pancreatic cancer cells in a three-dimensional tumor microenvironment.     

The novel synthetic inhibitor of matrix metalloproteinases Ro 28-2653 induces apoptosis in Dunning tumor cells

The effect of synthetic inhibitors of matrix metalloproteinases (MMP) has been shown against a variety of tumors in preclinical models. Ro 28-2653, a novel synthetic MMP inhibitor, is able to reduce tumor growth in orthotopic prostatic cancer in rats (R3327 Dunning tumor). However, at present this inhibitory mechanism in tumor inhibition in vivo can only be partly explained by the inhibition of the catalytic activity of MMPs overexpressed in cancereous tissue. Using the flow cytometric method, we have investigated the effect of various concentrations of Ro 28-2653 on the Dunning tumor cells with regard to the staining of F-actin and DNA as markers of apoptosis. In combination with fluorescence microscopy we detected the loss of F-actin and the degradation of internucleosomal DNA. This effect of Ro 28-2653 on apoptosis was dose- and time-dependent increasing with concentration between 10 and 100 g/ml as well as with time of treatment between 24 and 48 h.     

Does a-linolenic acid in combination with linoleic acid influence liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters?

Some fatty acids are reported to inhibit tumor growth of pancreatic carcinoma. However, it is still unknown if α-linolenic acid (ALA) and linoleic acid (LA) inhibit liver metastasis of ductal pancreatic adenocarcinoma. Therefore we studied the effect of these fatty acids on liver metastasis in the animal model of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic adenocarcinoma in Syrian hamsters. Since lipid peroxidation seems to be involved in carcinogenesis and metastasis, we further analyzed the intrahepatic concentration of thiobarbituric acid-reactive substances (TBARS) and activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD).We observed an increase in the incidence and the number of liver metastase in response to the combination of ALA and LA. This was accompanied by a decrease in hepatic GSH-Px activity and an increase in hepatic SOD activity and TBARS concentration. The increase in hepatic lipid peroxidation seems to be one possible mechanism of increasing liver metastasis in this study.     

MMP-2、MMP-9 及P53 的表达在肝移植后肿瘤复发与转移预测中 的价值研究

目的:探讨MMP-2、MMP-9及P53的表达在预测肝癌行肝移植后肿瘤复发与转移中的价值。方法:选择肝癌行全肝移植患者85例,应用免疫组化方法检测其切除的肝癌组织中MMP-2、MMP-9及P53的表达,并对患者进行移植术后随访,观察术后肝癌复发与转移情况。分析MMP-2、MMP-9及P53的表达与移植后肝癌复发与转移之间的关系和意义。结果:肝癌组织中MMP-2、MMP-9及P53阳性表达率均明显高于癌旁组织(P<0.01)。MMP-2表达与肝癌肿瘤直径、TNM分期、病理分级及门静脉癌栓显著相关性(P<0.05),MMP-9表达与肝癌肿瘤直径、TNM分期、门静脉癌栓及肿瘤包膜显著相关性(P<0.05),P53表达与肝癌肿瘤直径、门静脉癌栓及肿瘤包膜显著相关性(P<0.05)。MMP-2、MMP-9在未复发和转移组中的表达明显低于复发和转移组(P<0.05),而P53在两组间的表达差异无显著性(P>0.05)。肝癌组织中MMP-2、MMP-9高阳性表达均是预测肝癌患者肝移植后肿瘤复发和转移的独立预见因子,而P53未显示其具有预测意义。结论:MMP-2、MMP-9及P53在肝癌组织中呈高表达,MMP-2、MMP-9的表达水平可以有效预测肝癌患者肝移植后肿瘤复发和转移。     

Therapeutic efficacy of anti‐MMP9 antibody in combination with nab‐paclitaxel‐based chemotherapy in pre‐clinical models of pancreatic cancer

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti‐MMP9 antibody (αMMP9) was evaluated in combination with nab‐paclitaxel (NPT)‐based standard cytotoxic therapy in pre‐clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA‐Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2‐week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six‐week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti‐MMP9 antibody increased the levels of tumour‐associated IL‐28 (1.5‐fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti‐MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti‐MMP9 antibody can exert specific stroma‐directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.     

Does alpha-linolenic acid in combination with linoleic acid influence liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters?

Some fatty acids are reported to inhibit tumor growth of pancreatic carcinoma. However, it is still unknown if alpha-linolenic acid (ALA) and linoleic acid (LA) inhibit liver metastasis of ductal pancreatic adenocarcinoma. Therefore we studied the effect of these fatty acids on liver metastasis in the animal model of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic adenocarcinoma in Syrian hamsters. Since lipid peroxidation seems to be involved in carcinogenesis and metastasis, we further analyzed the intrahepatic concentration of thiobarbituric acid-reactive substances (TBARS) and activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD).We observed an increase in the incidence and the number of liver metastases in response to the combination of ALA and LA. This was accompanied by a decrease in hepatic GSH-Px activity and an increase in hepatic SOD activity and TBARS concentration. The increase in hepatic lipid peroxidation seems to be one possible mechanism of increasing liver metastasis in this study.     

MMP-2、MMP-7、MMP-9、TIMP-1及TIMP-2在乳腺癌组织中的表达及意义

目的:探讨基质金属蛋白酶及其抑制剂在乳腺癌组织中的表达及其与肿瘤浸润转移的关系,为乳腺癌的临床治疗及预后预测提供基础。方法:选择我院2012年5月至2014年5月收治的乳腺癌患者80例,对所选病例的乳腺癌组织、癌旁组织及正常乳腺组织样本进行检测。观察并比较不同乳腺组织中MMP-2,MMP-7、MMP-9、TIMP-1及TIMP-2 m RNA的表达水平。结果:与正常乳腺组织相比较,乳腺癌组织和癌旁组织中MMP-2、MMP-7、MMP-9,TIMP-1及TIMP-2 m RNA的表达显著增加,差异具有统计学意义(P0.05)。乳腺癌组织中MMP-2、MMP-7、MMP-9、TIMP-1及TIMP-2 m RNA的表达显著高于癌旁组织和正常组织,差异具有统计学意义(P0.05)。随着肿瘤范围扩大,MMP-2、MMP-7和MMP-9 m RNA的表达水平显著增加(P0.05),而TIMP-1和TIMP-2 m RNA表达无显著变化(P0.05)。随着淋巴结转移进展,MMP-2、MMP-7和MMP-9 m RNA的表达显著增加(P0.05),而TIMP-1和TIMP-2 m RNA无显著变化(P0.05)。结论:MMP-2、MMP-7、MMP-9、TIMP-1和TIMP-2的m RNA在乳腺癌组织中呈高表达,这可能与乳腺癌的发生和发展有关,而MMP-2、MMP-7和MMP-9可能有助于预测乳腺癌的侵袭行为。     

DNA ploidy and markovian analysis of neoplastic progression in experimental pancreatic cancer.

Computer-assisted analysis of DNA ploidy and nuclear morphology were used to elucidate changes in the cell nucleus that occur during the development of experimental pancreatic cancer. Ductal pancreatic adenocarcinoma was induced in 49 Syrian hamsters by SC injection of N-nitrosobis (2-oxopropyl) amine; twenty hamsters served as controls. Groups of animals were sacrificed every 4 weeks for 20 weeks and adjacent sections of pancreatic tissue were H&E and Feulgen-stained for light microscopy and computer assisted cytometry. Pancreatic ductal cells were classified as normal, atypical, or malignant; tissue inflammation (pancreatitis) was also noted when present. DNA ploidy and nuclear morphology evaluation (Markovian analysis) identified an atypical cell stage clearly distinguishable from either normal or malignant cells; pancreatitis preceded this atypia. The DNA ploidy histogram of these atypical cells revealed a major diploid peak and a minor aneuploid peak. The receiver operator characteristic curve areas for a logistic regression model of normal vs atypical cells was 0.94 and for atypical vs malignant was 0.98, numbers indicative of near-perfect discrimination among these three cell types. The ability to identify an atypical cell population should be useful in establishing the role of these cells in the progression of human pancreatic adenocarcinoma.     

Differential activity of matrix metalloproteinases (MMPs) during photoperiod induced uterine regression and recrudescence in Siberian hamsters (Phodopus sungorus)

Siberian hamsters adapt to seasonal changes by reducing their reproductive function during short days (SD). SD exposure reduces uterine mass and reproductive capacity, but underlying cellular mechanisms remain unknown. Because matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in uterine development, parturition, and postpartum remodeling, their expression in uterine tissue from Siberian hamsters undergoing photoperiod-mediated reproductive regression and recrudescence was investigated. Female hamsters were exposed to long day (LD, 16L:8D, controls) or SD (8L:16D) for 3-12 weeks (regression); a second group was exposed to SD or LD for 14 weeks and then transferred to LD for 0-8 weeks (recrudescence). Hamsters were euthanized, uteri collected, and homogenates analyzed by gelatin zymography or Western blotting for MMP and TIMP protein levels. Uterine weight decreased (67-75%) at SD weeks 12-14 and increased post-LD transfer (PT) reaching LD values by PT week 2. MMP-2, but not MMP-9 activity was reduced by SD week 12 or 14 but increased to LD levels at PT week 2. MMP-3 expression increased at SD week 9 compared to other SD and LD groups. MMP-14 and -13 protein levels decreased at SD week 3 but returned to LD levels by SD week 6. During recrudescence, MMP-3 (PT weeks 0-2), MMP-13 (PT week 4), and MMP-14 (PT weeks 2, 4) protein levels were higher than LD. TIMP-1 and 2 were present at low levels. Significant and differential variations in uterine MMP activity/expression during photoperiod-induced regression and recrudescence were observed. These changes likely reflect increases in tissue remodeling during both the adaptation to SD and the restoration of reproductive function.