Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The literature is divided on the role of these laminin-binding integrins in metastasis, with different studies indicating either pro- or antimetastatic functions. The opposing roles of the laminin-binding integrins in different settings might derive in part from their unusually robust associations with tetraspanin proteins. Tetraspanins organise integrins into multiprotein complexes within discrete plasma membrane domains termed tetraspanin-enriched microdomains (TEMs). TEM association is crucial to the strikingly rapid cell migration mediated by some of the laminin-binding integrins. However, emerging data suggest that laminin-binding integrins also promote the stability of E-cadherin-based cell-cell junctions, and that tetraspanins are essential for this function as well. Thus, TEM association endows the laminin-binding integrins with both pro-invasive functions (rapid migration) and anti-invasive functions (stable cell junctions), and the composition of TEMs in different cell types might help determine the balance between these opposing activities. Unravelling the tetraspanin control mechanisms that regulate laminin-binding integrins will help to define the settings where inhibiting the function of these integrins would be helpful rather than harmful, and may create opportunities to modulate integrin activity in more sophisticated ways than simple functional blockade.

/pdf/laminin-binding-integrins-and-their-tetraspanin-partners-as-4vjdnm8zju.pdf

Laminin-binding integrins and their tetraspanin partners as potential antimetastatic targets.

Objective Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag + strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host- H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7. Design Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag + strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2′-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry. Results Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori -induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori -infected individuals. Conclusions H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.

https://gut.bmj.com/content/gutjnl/early/2014/08/14/gutjnl-2014-307650.full.pdf

Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells

The opposing roles of laminin-binding integrins in cancer.

Maspin, a non-inhibitory member of the serine protease inhibitor superfamily, has been characterized as a tumor suppressor gene in multiple cancer types. Among the established anti-tumor effects of Maspin are the inhibition of cancer cell invasion, attachment to extracellular matrices, increased sensitivity to apoptosis, and inhibition of angiogenesis. However, while significant experimental data support the role of Maspin as a tumor suppressor, clinical data regarding the prognostic implications of Maspin expression have led to conflicting results. This highlights the need for a better understanding of the context dependencies of Maspin in normal biology and how these are perturbed in the context of cancer. In this review, we outline the regulation and roles of Maspin in normal and developmental biology while discussing novel evidence and emerging theories related to its functions in cancer. We provide insight into the immense therapeutic potential of Maspin and the challenges related to its successful clinical translation.

Maspin: molecular mechanisms and therapeutic implications

Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis. Further studies in these directions are necessary to better define the therapeutic implication of maspin.

/pdf/role-of-maspin-in-cancer-3nv3zo8rwt.pdf

Role of maspin in cancer

Objective: Maspin, a 42-kDa protein, belongs to the serpin family of protease inhibitors and is known to have tumor-suppressor function. In this study, we investigated the interrelationship between clinicopathologic findings and maspin expression in oral squamous cell carcinoma (OSCC).



Methods:  Using immunohistochemical techniques to examine the expression levels of maspin in OSCC, maspin expression in OSCC was detected in 46 (64.8%) of 71 cases. We also compared the clonicopathologic features of OSCC cases with maspin expression levels. Moreover, we examined expression of maspin in eight cell lines derived from OSCC using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting.



Results:  There was a significant correlation between decreased maspin expression and T-category (P < 0.01), lymph metastasis (P < 0.0001), and mode of invasion (P < 0.0001). Patients with positive maspin expression had a significantly better prognosis (P < 0.001). Lower expression of maspin was also seen in cell lines derived from grade 4D, which shows stronger invasive potential than other grades of OSCC.



Conclusion:  Maspin may be a useful marker to identify the potential for progression in OSCC.

/pdf/loss-of-maspin-is-a-negative-prognostic-factor-for-invasion-1lga8g3s52.pdf

Loss of maspin is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma.

The present study evaluated the relationship between alpha 3, alpha 6A, and beta 1 integrin expression in cancer cells at the invasive front of oral squamous cell carcinoma (OSCC) and survival rates, as well as the clinical and pathological characteristics. Sections of 100 specimens of primary OSCC were immunostained to assess alpha 3, alpha 6A, and beta 1 integrin expression in cancer cells at the invasive front. OSCC patients with higher expression levels of alpha 3, alpha 6A, and beta 1 integrin had significantly better prognosis than those with lower expression levels (median survival at low vs. high expression levels: alpha 3, 37.1 months vs. 55.7 months; alpha 6A , 38.3 months vs. 47.9 months; and beta 1, 26.1 months vs. 46.1 months) (P < 0.05). In addition, beta 1 integrin expression showed the highest correlation with clinical and pathological characteristics. This study concludes that alpha 3, alpha 6A, and beta 1 integrin expression in cancer cells at the invasive front are related to the mode of invasion and prognosis in OSCC.

Integrin expression levels correlate with invasion, metastasis and prognosis of oral squamous cell carcinoma.

J Oral Pathol Med (2011) 40: 693–698

Background:  Abnormalities in cell-cycle-controlling genes are important in the malignant transformation and proliferation of tumors. Among these genes, the tumor suppressor gene p53 is the most notable, and its mutations provide an indicator of tumor progression and prognosis. Proliferating cell nuclear antigen (PCNA) is a highly conserved nuclear protein that is expressed during cell replication and DNA repair. This study examined the expression of p53 and PCNA at the invasive front of oral squamous cell carcinomas (OSCC) by immunohistochemical staining, and investigated the relationship of these proteins to clinicopathological findings and prognosis.

Methods:  Fifty-nine biopsy cases of OSCC were examined by immunohistochemical staining. Clinicopathological data were gathered and patient survival was analyzed.

Results:  The p53 labeling index (p53-LI) and PCNA labeling index (PCNA-LI) were examined at the invasive front of the tumors. A high p53-LI (p53+) was observed in 17 of the 59 cases (28.8%) and a high PCNA-LI (PCNA+) was observed in 28 of the 59 cases (47.5%). Among the modes of cancer invasion, many of the p53+/PCNA+ cases could be confirmed as highly invasive cancer (P < 0.05). In addition, the p53+/PCNA+ cases showed a high risk of tumor recurrence compared with the other expression forms, and patients with p53+/PCNA+ had a worse prognosis than those with the other expression forms. High labeling indices of p53 and PCNA are associated with poor prognosis in patients with OSCC.

Conclusion:  We suggest that it is important to investigate the expression of p53 and PCNA at the invasive front of OSCC.

Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma: correlation with clinicopathological features and prognosis.

Claudin-7 belongs to the claudin family, which consists of 24 subtypes of essential tight junction (TJ) integral membrane proteins with molecular weights of 20-27 kDa. We investigated the interrelationship between clinicopathological findings and claudin-7 expression in oral squamous cell carcinoma (OSCC). Using immunohistochemical techniques to examine the expression levels of claudin-7 in 67 cases of OSCC, claudin-7 expression was detected in 35 (52.2%) of the 67 cases. We also compared the clinicopathological features of the OSCC cases with claudin-7 expression levels. Moreover, six cell lines with various invasive properties were investigated in vitro to compare mRNA and protein levels of claudin-7 using reverse transcription-polymerase chain reaction (RT-PCR) and the western blotting method. Decreased claudin-7 expression correlated significantly with T-category (p<0.05), lymph node metastasis (p<0.01), and mode of invasion (p<0.001). Patients with positive claudin-7 expression had a significantly better prognosis (p<0.05). Claudin-7 protein and mRNA levels were lower in the HOC313 and TSU cells, which have higher invasive potentials compared with other cell lines. These results suggest that loss of claudin-7 expression is associated closely with invasion and lymph metastasis and is an unfavorable prognostic factor in patients with OSCC.

/pdf/loss-of-claudin-7-is-a-negative-prognostic-factor-for-50q5veyvxi.pdf

Loss of claudin-7 is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma.

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Loss of maspin is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma.

Integrin expression levels correlate with invasion, metastasis and prognosis of oral squamous cell carcinoma.

Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma: correlation with clinicopathological features and prognosis.

Loss of claudin-7 is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma.