Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer.

How mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains an open question. Here we report the interaction between CFTR and an adherens junction molecule, AF-6/afadin, and its involvement in the development of colon cancer. We have found that CFTR and AF-6/afadin are co-localized at the cell-cell contacts and physically interact with each other in colon cancer cell lines. Knockdown of CFTR results in reduced epithelial tightness and enhanced malignancies, with increased degradation and reduced stability of AF-6/afadin protein. The enhanced invasive phenotype of CFTR-knockdown cells can be completely reversed by either AF-6/afadin over-expression or ERK inhibitor, indicating the involvement of AF-6/MAPK pathway. More interestingly, the expression levels of CFTR and AF-6/afadin are significantly downregulated in human colon cancer tissues and lower expression of CFTR and/or AF-6/afadin is correlated with poor prognosis of colon cancer patients. The present study has revealed a previously unrecognized interaction between CFTR and AF-6/afadin that is involved in the pathogenesis of colon cancer and indicated the potential of the two as novel markers of metastasis and prognostic predictors for human colon cancer.

FAP-α (Fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway.

BACKGROUND: Fibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase. Previous work has not satisfactorily explained both the suppression and promotion effects that have been observed in cancer. The purpose of this work was to investigate the role of FAP-α in human breast cancer. Expression of FAP-α was characterized in primary tumour samples and in cell lines, along with the effects of FAP-α expression on in vitro growth, invasion, attachment and migration. Furthermore the potential interaction of FAP-α with other signalling pathways was investigated. RESULTS: FAP-α was significantly increased in patients with poor outcome and survival. In vitro results showed that breast cancer cells over expressing FAP-α had increased growth ability and impaired migratory ability. The growth of MDA-MB-231 cells and the adhesion and invasion ability of both MCF-7 cells and MDA-MB-231 cells were not dramatically influenced by FAP-α expression. Over-expression of FAP-α resulted in a reduction of phosphorylated focal adhesion kinase (FAK) level in both cells cultured in normal media and serum-free media. An inhibitor to FAK restored the reduced motility ability of both MCF-7exp cells and MDA-MB-231exp cells and prevented the change in phosphorylated FAK levels. However, inhibitors to PI3K, ERK, PLCΥ, NWASP, ARP2/3, and ROCK had no influence this. CONCLUSIONS: FAP-α in significantly associated with poor outcome in patients with breast cancer. In vitro, FAP-α promotes proliferation and inhibits migration of breast cancer cells, potentially by regulating the FAK pathway. These results suggest FAP-α could be a target for future therapies.

The role of SIPA1 in the development of cancer and metastases (Review).

Cancer is a leading cause of mortality and the majority of deaths are due to metastases. Many molecules have been implicated in the development of metastases. Signal induced proliferation associated protein 1 (SIPA1), a mitogen-inducible gene, has been demonstrated to be involved in the metastasis of various solid tumours and may indicate a poor prognosis. Polymorphisms of SIPA1 can be associated with several different types of cancer and interactions between SIPA1 and binding molecules integrate a series of cellular functions, which may promote the development and metastasis of cancer. The mechanisms by which SIPA1 promotes the development and metastasis of cancer varies among tumour types. The present review describes the structure, function and regulation of SIPA1 and focuses on its role in cancer metastasis. Possibilities for future research and the clinical application of SIPA1 are also discussed.

Correlation of TERT and Stem Cell Markers in the Context of Human Breast Cancer.

BACKGROUND: Telomerase reverse transcriptase (TERT) has a well-known role in carcinogenesis due to its functions in inducing cell immortality and preventing senescence. In this study, the relationships between TERT and a panel of known stem cell markers was examined in order to direct future enquiries into the role of 'stem-ness' in human breast cancer. MATERIALS AND METHODS: Breast cancer tissues (n=124) and adjacent normal tissues (n=30) underwent reverse transcription and quantitative polymerase chain reaction. Transcript levels were analyzed for the correlation with that of TERT. RESULTS: A significant direct correlation was found in cancerous tissue between TERT and BMI1 proto-oncogene polycomb ring finger 4 (BMI1; n=88, p<0.001), nestin (NES; n=88, p<0.001), POU domain, class 5, transcription factor 1 (POU5F1; n=88, p<0.001), aldehyde dehydrogenase 1 family member A2 (ALDH1A2; n=87, p=0.0298), cyclin-dependent kinase inhibitor 1A (CDKN1A; n=88, p<0.001), integrin subunit beta 1 (ITGNB1; n=88, p<0.001), integrin subunit alpha 6 (ITGA6; n=88, p<0.001), cluster of differentiation antigen 24 (CD24; n=88, p=0.0114), MET proto-oncogene (MET; n=78, p<0.001) and noggin (NOG; n=88, p<0.001). CONCLUSION: The evidence presented in this article of possible interactions between TERT and a discrete subset of known stem cell markers would significantly contribute to further enquiries regarding clonal dynamics in the context of human breast cancer.

Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma.

The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types.

Effect of human fibroblast-derived dermis on expansion of tissue from venous leg ulcers.

Novel approaches to healing of chronic wounds, such as venous leg ulcers, include the use of tissue-engineered skin substitutes, e.g., human fibroblast-derived dermis. The exact mechanisms of action of these products and their effects on wound healing at a cellular level are yet to be fully defined. The aim of our study was to evaluate the potential effects of human fibroblast-derived dermis on the healing of chronic wounds using an experimental model. We used a tissue expansion model to examine the effect of human fibroblast-derived dermis on the growth of human tissue biopsied from venous leg ulcers. Further characterization of the cytokine profile produced by human fibroblast-derived dermis in culture was performed using enzyme-linked immunosorbent assay techniques. Addition of medium conditioned with human fibroblast-derived dermis significantly increased the outgrowth of cells from venous leg ulcer biopsies (p = 0.001). We detected bioactive levels of hepatocyte growth factor/scatter factor and interleukin-8 in media conditioned with human fibroblast-derived dermis. Therefore, conditioned media from human fibroblast-derived dermis enhances ex vivo expansion of tissue taken from chronic venous leg ulcers, and contains potent angiogenic factors. These experimental findings may explain the enhanced healing seen with clinical applications of human fibroblast-derived dermis on chronic wounds.