Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer

Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
British Journal of Cancer (Impact Factor: 4.84). 08/2011; 105(5):666-72. DOI: 10.1038/bjc.2011.295
Source: PubMed


Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer. In this study, we investigated the prognostic impact of PODXL expression in colorectal cancer (CRC).
Using tissue microarrays and immunohistochemistry, PODXL expression was evaluated in 536 incident CRC cases from a prospective, population-based cohort study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the impact of PODXL expression on cancer-specific survival (CSS) and overall survival (OS).
High PODXL expression was significantly associated with unfavourable clinicopathological characteristics, a shorter CSS (hazard ratio (HR)=1.98; 95% confidence interval (CI) 1.38-2.84, P<0.001) and 5-year OS (HR=1.85; 95% CI 1.29-2.64, P=0.001); the latter remaining significant in multivariate analysis (HR=1.52; 95% CI 1.03-2.25, P=0.036). In addition, in curatively resected stage III (T1-4, N1-2, M0) patients (n=122) with tumours with high PODXL expression, a significant benefit from adjuvant chemotherapy was demonstrated (p(interaction) =0.004 for CSS and 0.015 for 5-year OS in multivariate analysis).
Podocalyxin-like 1 expression is an independent factor of poor prognosis in CRC. Our results also suggest that PODXL may be a useful marker to stratify patients for adjuvant chemotherapy.

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    • "Podocalyxin also plays a more general role in directing the morphogenesis of tubular and glandular epithelia by facilitating the formation of nonadhesive apical membrane domains during lumen formation161718. Interestingly, Mostov and colleagues recently demonstrated that podocalyxin can also cause normal epithelial cells to become collectively invasive in three-dimensional (3-D) culture when polarity cues are actively disrupted such that apical membrane domains and lumens do not form efficiently[19]. Podocalyxin is highly expressed in a number of human tumors, most of which are epithelially derived, with varying degrees of prognostic significance2021222324252627282930313233. In the case of invasive breast cancer, podocalyxin overexpression is an independent marker of poor outcome[13]. "
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    ABSTRACT: Background: Overexpression of the transmembrane sialomucin podocalyxin, which is known to play a role in lumen formation during polarized epithelial morphogenesis, is an independent indicator of poor prognosis in a number of epithelial cancers, including those that arise in the breast. Therefore, we set out to determine if podocalyxin plays a functional role in breast tumor progression. Methods: MCF-7 breast cancer cells, which express little endogenous podocalyxin, were stably transfected with wild type podocalyxin for forced overexpression. 4T1 mammary tumor cells, which express considerable endogenous podocalyxin, were retrovirally transduced with a short hairpin ribonucleic acid (shRNA) targeting podocalyxin for stable knockdown. In vitro, the effects of podocalyxin on collective cellular migration and invasion were assessed in two-dimensional monolayer and three-dimensional basement membrane/collagen gel culture, respectively. In vivo, local invasion was assessed after orthotopic transplantation in immunocompromised mice. Results: Forced overexpression of podocalyxin caused cohesive clusters of epithelial MCF-7 breast tumor cells to bud off from the primary tumor and collectively invade the stroma of the mouse mammary gland in vivo. This budding was not associated with any obvious changes in histoarchitecture, matrix deposition or proliferation in the primary tumour. In vitro, podocalyxin overexpression induced a collective migration of MCF-7 tumor cells in two-dimensional (2-D) monolayer culture that was dependent on the activity of the actin scaffolding protein ezrin, a cytoplasmic binding partner of podocalyxin. In three-dimensional (3-D) culture, podocalyxin overexpression induced a collective budding and invasion that was dependent on actomyosin contractility. Interestingly, the collectively invasive cell aggregates often contained expanded microlumens that were also observed in vivo. Conversely, when endogenous podocalyxin was removed from highly metastatic, but cohesive, 4T1 mammary tumor cells there was a decrease in collective invasion in three-dimensional culture. Conclusions: Podocalyxin is a tumor cell-intrinsic regulator of experimental collective tumor cell invasion and tumor budding.
    Preview · Article · Dec 2016 · Breast cancer research: BCR
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    • "Because of apparent difference in PODXL expression depending on antibodies used we decided to compare PODXL expression, by our own in-house HES9 mAb and by a commercially available polyclonal antibody (pAb) used in other studies [17,18], case-by-case in a cohort of 840 CRC patients. "
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    ABSTRACT: Background Podocalyxin (PODXL) is a transmembrane sialomucin, whose aberrant expression and/or allelic variation associates with poor prognosis and unfavourable clinicopathological characteristics in different cancers. Membranous expression of PODXL has been suggested to be an independent marker of poor prognosis in colorectal cancer (CRC), and previously by an in-house monoclonal antibody, we showed that also cytoplasmic overexpression of PODXL predicts poor prognosis. The aim of this study was to compare two PODXL antibodies with different epitopes case-by-case in CRC patients. Methods Of 840 consecutively operated CRC patients from Helsinki University Central Hospital, PODXL expression by polyclonal HPA 2110 antibody was evaluated from 780. Associations of PODXL expression with clinicopathological parameters and the impact of PODXL expression on survival were assessed. Kappa-value was used to assess the comparability of the two antibodies. Results Membranous PODXL expression associated with unfavourable clinicopathological parameters and with higher risk for disease-specific death from CRC within 5 years (unadjusted hazard ratio (HR) = 1.90; 95% confidence interval (CI) (1.32-2.75); adjusted HR = 1.64; 95% CI (1.11-2.43)). The comparability of expressions by the two antibodies was low (kappa =0.219, standard error 0.060, p < 0.0001). Combination of two antibodies identified a group of patients with even worse prognosis (unadjusted HR = 6.00; 95% CI (3.27-13.0); adjusted HR = 2.14; 95% CI (1.12-4.07)). Conclusion Membranous expression by the polyclonal PODXL antibody and cytoplasmic overexpression by the monocolonal PODXL antibody are both independent markers of poor prognosis, but they recognise different groups of patients, both of which have poor prognosis. The combined use of the antibodies reveals a group with an even worse prognosis. The biological reasons for the difference between antibodies warrant further studies.
    Full-text · Article · Jul 2014 · BMC Cancer
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    • "Tissue microarrays (TMAs) had been constructed as previously described [29,30]. In brief, two 1.0 mm cores were taken from each tumour and mounted in a new recipient block using a semi-automated arraying device (TMArrayer, Pathology Devices, Westminster, MD, USA). "
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    ABSTRACT: Background: Postmenopausal hormone therapy (HRT) and oral contraceptive (OC) use have in several studies been reported to be associated with a decreased colorectal cancer (CRC) risk. However, data on the association between HRT and OC and risk of different clinicopathological and molecular subsets of CRC are lacking. The aim of this molecular pathological epidemiology study was therefore to evaluate the associations between HRT and OC use and risk of specific CRC subgroups, overall and by tumour site. Method: In the population-based prospective cohort study Mamö Diet and Cancer, including 17035 women, 304 cases of CRC were diagnosed up until 31 December 2008. Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status had previously been assessed in tissue microarrays with tumours from 280 cases. HRT was assessed as current use of combined HRT (CHRT) or unopposed oestrogen (ERT), and analysed among 12583 peri-and postmenopausal women. OC use was assessed as ever vs never use among all women in the cohort. A multivariate Cox regression model was applied to determine hazard ratios for risk of CRC, overall and according to molecular subgroups, in relation to HRT and OC use. Results: There was no significantly reduced risk of CRC by CHRT or ERT use, however a reduced risk of T-stage 1-2 tumours was seen among CHRT users (HR: 0.24; 95% CI: 0.09-0.77).Analysis stratified by tumour location revealed a reduced overall risk of rectal, but not colon, cancer among CHRT and ERT users, including T stage 1-2, lymph node negative, distant metastasis-free, cyclin D1 - and p53 negative tumours.In unadjusted analysis, OC use was significantly associated with a reduced overall risk of CRC (HR: 0.56; 95% CI: 0.44-0.71), but this significance was not retained in adjusted analysis (HR: 1.05: 95% CI: 0.80-1.37). A similar risk reduction was seen for the majority of clinicopathological and molecular subgroups. Conclusion: Our findings provide information on the relationship between use of HRT and OC and risk of clinicopathological and molecular subsets of CRC.
    Full-text · Article · May 2014 · BMC Cancer
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