Journal of Pathology

The transforming growth factor‐β (TGF‐β) signalling pathway plays a critical and dual role in the progression of human cancer. During the early phase of tumour progression, TGF‐β acts as a tumour suppressor, exemplified by deletions or mutations in the core components of the TGF‐β signalling pathway. On the contrary, TGF‐β also promotes processes that support tumour progression such as tumour cell invasion, dissemination, and immune evasion. Consequently, the functional outcome of the TGF‐β response is strongly context‐dependent including cell, tissue, and cancer type. In this review, we describe the molecular signalling pathways employed by TGF‐β in cancer and how these, when perturbed, may lead to the development of cancer. Concomitantly with our increased appreciation of the molecular mechanisms that govern TGF‐β signalling, the potential to therapeutically target specific oncogenic sub‐arms of the TGF‐β pathway increases. Indeed, clinical trials with systemic TGF‐β signalling inhibitors for treatment of cancer patients have been initiated. However, considering the important role of TGF‐β in cardiovascular and many other tissues, careful screening of patients is warranted to minimize unwanted on‐target side effects. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Coronin‐3 (coronin‐1C), a homotrimeric F‐actin binding protein, has been shown to be important for cell migration and brain morphogenesis. Here, we present for the first time a detailed analysis of the expression pattern of coronin‐3 in human brain tumours and demonstrate that coronin‐3 expression correlates with malignant phenotype in diffuse gliomas. In general, the expression of coronin‐3 varies in different brain tumour entities. However, in diffuse gliomas, the number of coronin‐3 expressing tumour cells correlates with the degree of malignancy. High‐grade gliomas, such as anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas and glioblastomas, show high numbers of tumour cells positive for coronin‐3, while diffuse low‐grade gliomas, such as diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas, exhibit low numbers of coronin‐3‐positive tumour cells. In order to explore and verify a contribution of coronin‐3 to the malignant phenotype of diffuse gliomas, we employed an efficient shRNA‐mediated coronin‐3 knockdown in U373 and A172 human glioblastoma cells. Coronin‐3 knockdown glioblastoma cells exhibited reduced levels of cell proliferation, cell motility and invasion into extracellular matrix compared to control cells. Together, our findings demonstrate evidence for a contribution of coronin‐3 expression in the malignant progression of diffuse gliomas. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Persistent infection with a high‐risk human papillomavirus (hrHPV) is generally accepted as a necessary cause of cervical cancer. However, cervical cancer is a rare complication of an hrHPV infection since most such infections are transient, not even giving rise to cervical lesions. On average, it takes 12–15 years before a persistent hrHPV infection may ultimately, via consecutive premalignant stages (ie CIN lesions), lead to an overt cervical carcinoma. This argues that HPV‐induced cervical carcinogenesis is multi‐step in nature. In this review, the data from hrHPV‐mediated in vitro transformation studies and those obtained from analysis of clinical specimens have been merged into a cervical cancer progression model. According to this model, a crucial decision maker in the early stages following infection involves individual susceptibility for certain HPV types depending on the genetic make‐up of immune surveillance determinants. Once a CIN lesion has developed, altered transcriptional regulation of the viral E6/E7 oncogenes, resulting in genomic instability and distinguishing the process of cell transformation from a productive viral infection, probably provides the subsequent important step towards malignancy. The additional (epi)genetic alterations that subsequently accumulate in high‐grade CIN lesions may result in overt malignancy via immortality and growth conditions that gradually become less sensitive to growth‐modulating influences mediated by cytokines and cell–cell and cell–matrix adhesions. The potential implications of hrHPV testing and some other biomarkers deduced from this model for cervical screening and the clinical management of CIN disease are also discussed. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The association of autoimmune phenomena with atherosclerosis suggests that plaques may contain specialized antigen‐presenting cells, dendritic cells (DCs). DC‐SIGN is a C‐type lectin expressed by DCs. This study assessed whether human atherosclerotic plaques expressed DC‐SIGN and several other macrophage/DC markers. Plaques from human coronary and carotid arteries and aorta contained DC‐SIGN‐immunoreactive cells. Double‐labelling showed co‐expression of DC‐SIGN and macrophage/DC lineage markers CD14, CD68, HLA‐DR, and S100. There was no immunoreactivity for the DC activation markers CD83 or CMRF‐44. Since DC‐SIGN mediates adhesion to T‐lymphocytes and endocytosis, its expression in atherosclerotic plaques may have functional implications. Activated DCs migrate quickly from areas of inflammation to regional lymph nodes, possibly explaining the paucity of activated DCs in atherosclerotic plaques. In conclusion, this study has shown that DC‐SIGN is expressed in atherosclerosis. Copyright © 2002 John Wiley & Sons, Ltd.

A variety of analyses, including fluorescence in situ hybridization (FISH), quantitative PCR (qPCR) and array CGH (aCGH), have been performed on a series of chordomas from 181 patients. Twelve of 181 (7%) tumours displayed amplification of the T locus and an additional two cases showed focal amplification; 70/181 (39%) tumours were polysomic for chromosome 6, and 8/181 (4.5%) primary tumours showed a minor allelic gain of T as assessed by FISH. No germline alteration of the T locus was identified in non‐neoplastic tissue from 40 patients. Copy number gain of T was seen in a similar percentage of sacrococcygeal, mobile spine and base of skull tumours. Knockdown of T in the cell line, U‐CH1, which showed polysomy of chromosome 6 involving 6q27, resulted in a marked decrease in cell proliferation and morphological features consistent with a senescence‐like phenotype. The U‐CH1 cell line was validated as representing chordoma by the generation of xenografts, which showed typical chordoma morphology and immunohistochemistry in the NOD/SCID/interleukin 2 receptor [IL2r]$\gamma^{\rm{null}}$ mouse model. In conclusion, chromosomal aberrations resulting in gain of the T locus are common in sporadic chordomas and expression of this gene is critical for proliferation of chordoma cells in vitro. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemokines (chemo‐attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body. Cancer cells acquire the ability to subvert the chemokine system, such that these molecules and their receptors become important regulators of cell movement into and out of the tumour microenvironment and major players in cancer biology. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.