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GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results...
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... 4 provides the coefficients of elevated GP88 with Wald P-value and hazard ratios (HR) and shows that high GP88 is associated with an HR of 5.93 for DFS and 2.45 for OS. Univariate analysis shows that other predic- tors of survival were tumor size, tumor grade, age, dis- ease stage, lymph node status and treatment for DFS (Table 5) and/or OS (Table 6). A major question is whether the information from GP88 expression dupli- cates, or is independent of, that contained in the other conventional risk factors. ...
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... between survival and GP88 corrected for the covariate. The results of Table 5 show that there was a marginally significant interaction of GP88 with tumor size in DFS, but no hint of interaction between GP88 and any of the other indicators investigated, such as tumor grade, lymph node status, disease stage, PR expression, age, ethnicity and treatments. Similar obser- vations were obtained for OS in Table 6. ...
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... data point out that GP88 remains highly significant even after adjustment for each of these covariates. Having GP88 = 3+ corresponds to a hazard ratio for recurrence between 4.8 and 6.2, after correction for the covariates (Table 5). Elevated GP88 corresponds to a hazard ratio between 2.0 and 2.7 for decrease in OS (Table 6). ...
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Citations
... In breast cancer, progranulin has been proposed as a diagnostic, predictive and prognostic marker, as progranulin levels correlated with tumor angiogenesis, tumor size and the presence of metastasis in lymph nodes [107][108][109][110][111][112][113]. In addition, in patients with estrogen receptor-positive invasive ductal carcinoma, high progranulin levels in breast tumor tissue sections inversely correlated with disease-free tissue and overall survival rates and were predictive of recurrence risk and increased mortality [109]. ...
... In breast cancer, progranulin has been proposed as a diagnostic, predictive and prognostic marker, as progranulin levels correlated with tumor angiogenesis, tumor size and the presence of metastasis in lymph nodes [107][108][109][110][111][112][113]. In addition, in patients with estrogen receptor-positive invasive ductal carcinoma, high progranulin levels in breast tumor tissue sections inversely correlated with disease-free tissue and overall survival rates and were predictive of recurrence risk and increased mortality [109]. Progranulin serum levels were higher in breast cancer patients when compared to healthy individuals and were predictive of recurrence in hormone-receptor-positive breast cancer patients treated with tamoxifen [114]. ...
Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.
... This is consistent with our findings. In breast cancer, the tissue level of PGRN predicts the risk of recurrence of ERpositive invasive ductal carcinoma [46]. Monoclonal antibody against PGRN inhibits the growth of hepatocellular carcinoma in nude mice [47]. ...
Helicobacter pylori, a group 1 carcinogen, colonizes the stomach and affects the development of stomach diseases. Progranulin (PGRN) is an autocrine growth factor that regulates multiple cellular processes and plays a tumorigenic role in many tissues. Nevertheless, the mechanism of action of PGRN in gastric cancer caused by H. pylori infection remains unclear. Here, we investigated the role of PGRN in cell cycle progression and the cell proliferation induced by H. pylori infection. We found that the increased PGRN was positively associated with CDK4 expression in gastric cancer tissue. PGRN was upregulated by H. pylori infection, thereby promoting cell proliferation, and that enhanced level of proliferation was reduced by PGRN inhibitor. CDK4, a target gene of PGRN, is a cyclin-dependent kinase that binds to cyclin D to promote cell cycle progression, which was upregulated by H. pylori infection. We also showed that knockdown of CDK4 reduced the higher cell cycle progression caused by upregulated PGRN. Moreover, when the PI3K/Akt signaling pathway (which is promoted by PGRN) was blocked, the upregulation of CDK4 mediated by PGRN was reduced. These results reveal the potential mechanism by which PGRN plays a major role through CDK4 in the pathological mechanism of H. pylori infection.
... It has been shown that PGRN is able to bind to the receptor Tyrosine Kinase, EPH receptor A2 (EphA2) and activate MAPK and AKT signalling pathways (Zanocco-Marani et al., 1999;Neill et al., 2016). In relation with the mitogenic and angiogenic functions, PGRN has been associated to several cancers, generally with a direct correlation between the PGRN levels and cancer malignancy Abrhale et al., 2011;Serrero et al., 2012;Edelman et al., 2014). In the other hand, reducing PGRN levels by direct antibody treatment against PGRN have a tumour suppressor effect (Ho et al., 2008). ...
Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.
... According to these results, it seems that the addition of PGRN inhibitor to the chemotherapy regimen of breast cancer patients (especially in TNBC) can lead to an optimal response to treatment. On the other hand, although PGRN is linked to lymph node metastasis, tumor size and TNM staging system, its expression is independent of the demographic characteristics of patients (age, sex and ethnicity), tumor characteristics of patients (tumor size, tumor grade, progesterone receptors status, disease stage, and lymph node status) and type of treatment [35,104]. Therefore, it can be considered an independent prognostic factor regardless of age and stage in breast cancer patients. ...
... The IHC staining method for measuring PGRN has advantages such as fast, reproducible and cost-effective way [103]. In this method, the PGRN expression levels can be scored from negative to + 3, where Serrero et al. reported that the breast cancer patients with PGRN expression level of + 3 had a 5.9 and 2.5-fold odds ratio of disease recurrence and mortality hazard, respectively, compared with those with lower PGRN expression level [104]. Given the undeniable role of SORT1 in the initiation of PRGN-induced mechanisms, the combined evaluation of SORT1 along with PRGN can be a strong prognostic factor in predicting clinical outcomes of breast cancer [67]. ...
Breast cancer constitute a common type of oncological disease with a highlighted mortality rate. In recent years, researchers have introduced progranulin (PGRN) as an novel potential biomarker and associated its function with higher risk factor for development of breast cancer. The present review article collects evidence on the association of PGRN with clinicopathological features and drug resistance in the patients with breast cancer. The results of this study suggested the use of routine determination of PGRN in the clinic as a reliable biomarker for screening people at high risk or as early indication of breast cancer. Targeting PGRN and its associated signaling pathways and receptors, such as sortilin (SORT1), could also cover a novel therapeutic strategy in the breast cancer.
... It also has been demonstrated that PGRN upregulation is closely correlated with the worse progression-free survival of patients with glioblastoma (96). Moreover, PGRN levels are important for predicting recurrence in cancer patients (97). Recurrence probability is much higher in breast cancer patients with higher PGRN serum levels (98). ...
Progranulin (PGRN) is an autocrine growth factor and has important effects on regulation of cell growth, motility, tissue repair and embryonic development. Recent years, several researches found the expression of PGRN was at higher levels in a number of cancer cells and its high levels are associated with poor outcome of patients. More and more studies investigated the role of PGRN in cancer and found PGRN exerted various biological functions in cancer cells, such as promoting proliferation, inhibiting apoptosis, inducing migration and invasion of cells, accelerating angiogenesis and enhancing the effectiveness of chemoresistance and radiation. Now the effects of PGRN have been demonstrated in several cancers, including breast cancer, lung cancer, and bladder cancer. In addition, several signaling pathways and molecules are involved in the effects of PGRN on cancer cells, including Akt, mitogen-activated protein kinase (MAPK), vascular endothelial growth factor (VEGF) and cyclin D1. Therefore, PGRN is probably a significant diagnostic and prognostic biomarker for cancer and may be a potential target for anti-cancer therapy. Here, we reviewed the advancing field of PGRN in cancer as well as several signaling pathways activated by PGRN and confirmed PGRN is a key role in cancer. Moreover, future studies are still necessary to elucidate the biological functions and signaling pathways of PGRN in cancer.
... GP88, named after its molecular weight at~88 kDa on Western immunoblots due to glycosylation, is physiologically a growth factor that regulates cell proliferation and wound repair, but pathologically it is also a component of the tumorigenesis machinery for different cancers [20][21][22][23]. Increased GP88 expression has been reported in breast cancer, brain tumors, non-small cell lung cancer, ovarian cancer, renal carcinoma, hepatocellular carcinoma, prostate cancer, colorectal cancer and hematological cancers [22,[24][25][26][27][28][29][30]. An association between increased GP88 protein expression and a poor prognosis has been reported for breast cancer, ovarian cancer, non-small cell lung carcinoma, lymphomas, esophageal cancer, prostate cancer, and colorectal cancer [25,26,[28][29][30][31][32]. ...
... Increased GP88 expression has been reported in breast cancer, brain tumors, non-small cell lung cancer, ovarian cancer, renal carcinoma, hepatocellular carcinoma, prostate cancer, colorectal cancer and hematological cancers [22,[24][25][26][27][28][29][30]. An association between increased GP88 protein expression and a poor prognosis has been reported for breast cancer, ovarian cancer, non-small cell lung carcinoma, lymphomas, esophageal cancer, prostate cancer, and colorectal cancer [25,26,[28][29][30][31][32]. GP88 expression is also correlated with resistance to anti-estrogen therapy in breast cancer patients [25,33] and platinum-based chemotherapy in non-small cell lung cancer patients [34]. ...
... An association between increased GP88 protein expression and a poor prognosis has been reported for breast cancer, ovarian cancer, non-small cell lung carcinoma, lymphomas, esophageal cancer, prostate cancer, and colorectal cancer [25,26,[28][29][30][31][32]. GP88 expression is also correlated with resistance to anti-estrogen therapy in breast cancer patients [25,33] and platinum-based chemotherapy in non-small cell lung cancer patients [34]. ...
Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. > 0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.
... Previous pathological studies showed that PGRN is expressed in invasive ductal carcinoma, but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. 4 In Rheumatoid Arthritis patients, the levels of circulating serum PGRN have been measured and were found to be higher than those in age-matched healthy controls. 1 The PGRN levels were higher in the serum of patients with lymphoid malignancies than in healthy controls. ...
Background
Elevated serum progranulin (PGRN) levels have been associated with a wide range of different human malignancies. However, data available on the role of PGRN in hematological malignancies are limited.
Methods
Measurement of the PGRN level in serum of adult de novo acute myeloid leukemia (AML) patients using enzyme-linked immunosorbent assay (ELISA) was performed.
Results
The mean serum PGRN level in AML patients was higher than that in controls (346.08 pg/ml ± 64.46 vs 155 pg/ml ± 63 respectively; p = 0.001). After a mean duration of follow-up equaling 140 days, patients with high serum PGRN (i.e., higher than 370.5 pg/ml) had inferior overall survival (OS) in comparison to patients with low serum PGRN (i.e., lower than 370.5 pg/ml) (OS = 25% vs 60.7%, mean survival = 107 days vs 256.5 days, p = 0.007). On the other hand, remitted patients on day 28 with high serum PGRN (i.e., higher than 307.5 pg/ml) did not differ from those with low serum PGRN (i.e., lower than 307.5 pg/ml) regarding disease-free survival (DFS) (DFS = 78.6% vs. 87.5%, mean survival = 301.3 days vs. 283.5 days, p = 0.789). Moreover, the serum PGRN level was associated with inferior OS (p = 0.024) on multivariate analysis.
Conclusion
Adult de novo AML patients have elevated serum PGRN levels and a high PGRN level is associated with an inferior OS.
... The role of PGRN/GP88 as a driver and marker of tumor aggressiveness has been investigated in BC [20]. (1) in ER + BC cells, GP88 stimulates proliferation and confers estrogen independence and anti-estrogen and aromatase inhibitors resistance [21][22][23][24]; (2) in Her-2 overexpressing BC, PGRN/GP88 stimulates Her-2 phosphorylation and confers trastuzumab resistance [25] with stimulating c-myc expression and phosphorylation [26]; (3) PGRN/GP88 is expressed in 80% invasive ductal carcinoma (IDC) and is negative in normal mammary tissue [27]; (4) in ER + IDC, PGRN/GP88 expression is an independent prognostic indicator of recurrence and survival [28]; (5) PGRN/GP88 circulating level is elevated in ER + patients on tamoxifen [29] and in metastatic BC patients, increased PGRN/GP88 is associated with disease progression and response to therapy [30]; and (6) high PGRN/GP88 expression correlates with reduced survival of TNBC patients [31]. Thus, progranulin represents a potential therapeutic target for TNBC [32][33][34]. ...
Background
Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC.Methods
The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo.ResultsInhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo.ConclusionPGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.
... In fact, progranulin present in serum has been demonstrated to predict recurrence in hormone positive (ERα and progesterone receptor (PR) positive) breast cancer patients during tamoxifen treatment [13]. In addition, high levels of progranulin expression in tumors from patients with ERα positive invasive ductal carcinoma (IDC) is associated with increased risk of recurrence [14]. Further, Li and colleagues demonstrated that progranulin tumor expression was significantly higher in tumors from triple negative breast cancer patients without presence of lymph node metastasis [15]. ...
... In addition, progranulin is involved in various biological processes, such as wound healing, tumorigenesis, inflammation and has been associated with various neurological diseases [16][17][18][19][20][21][22][23]. The fact that high progranulin has been observed in both tissue and serum of various cancer types compared to normal tissue [9,12,13,[24][25][26][27][28][29][30] suggests that progranulin may be a relevant biomarker in breast cancer, as well as in other cancer types [13,14]. ...
... Previous reports have associated high progranulin expression with ERα negative patients [19] as well as a predictive marker for recurrence in ERα positive breast cancer [14]. We recently showed that progranulin secretion increased in ERα positive breast cancer when cells were subjected to hypoxia, whereas ERα negative breast cancer cells had constitutive high secretion of progranulin [7]. ...
Background
The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients.
Methods
We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers.
Results
Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317–3.637, p =0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance.
Conclusion
Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.
... Peripheral PGRN levels were positively correlated with both estrogen and progesterone in pregnant women (Todoric et al., 2012). Serum PGRN level was a predictive parameter for recurrence and mortality in hormone-receptor positive breast cancer patients (Koo et al., 2012;Serrero et al., 2012). PGRN acts as a suppressor of inflammatory process by blocking tumor necrosis factor (TNF)-α signaling by binding to TNF receptor 2 (Zhao et al., 2015). ...
Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24–26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R² = 0.75) and interleukin-8 (R² = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.
