γδ T cells could promote cancer progression of HPV-induced lesions

Conference (2012, June 02)

Oncogenic human papillomavirus could directly interact with Natural Killer cells

Poster (2012, May 04)

INTRA-TUMORAL HETEROGENEITY AND RATIONAL SELECTION OF ANTIGENS FOR TARGETED THERAPY OF LIVER METASTASES

in Acta Chirurgica Belgica (2012, May), 112(3), 8953

Objectives: Targeted therapies of liver metastases are gaining a major stake in current and future treatment options. However, the malignant lesions are heterogeneous in nature offering niches for cancer ... [more ▼]

Objectives: Targeted therapies of liver metastases are gaining a major stake in current and future treatment options. However, the malignant lesions are heterogeneous in nature offering niches for cancer cells causing treatment resistance and relapse. Therefore, a rational strategy is needed to select targetable antigens that would overcome this intra-tumoral heterogeneity. Methods: After ethical committee approval, 48 fresh liver metastases of colorectal origin were prospectively collected from patients undergoing liver resection. Here we macroscopically divided the lesion in different zones and generated a unique quantitative picture of the proteome heterogeneity in colorectal carcinoma liver metastases. Particular focus was laid on accessible proteins, a protein subclass comprising cell membrane associated and extracellular proteins. Accordingly, the tissues were ex-vivo biotinylated, affinity purified and analyzed for each zone separately using nano-UPLC-MSe proteomics technique. In total over 1500 unique proteins were statistically divided into different patterns of expression. Results: We have generated a quantitative picture of the proteome heterogeneity in colorectal carcinoma liver metastases. The study offers insight into novel targets but also antigens against which the antibodies are already involved in clinical trials or treatment of liver metastases. Extensive clustering and validation experiments highlight novel markers that offer the potential to homogeneously cover the metastatic lesion and become better targets. Conclusions: Two such antigens, LTBP2 and TGFBI were selected for functional analysis in colorectal carcinoma cells. In vitro and in vivo experiments showed that in particular TGFBI is relevant for migration and proliferation capacity of colorectal cancer cells. The suppression of this protein led to significant inhibition of tumor growth, crystalizing it as bona fide target for the development of anti-metastases therapies. [less ▲]

Natural Killer cells - role in local tumor growth and metastasis

in Biologics: Targets and Therapy (2012)

Historically, the name of Natural Killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the seventies to date, accumulating data highlighted the importance of NK cells in ... [more ▼]

Historically, the name of Natural Killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the seventies to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced anti-tumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis and their implications in anti-tumor immunotherapies via cytokines, antibodies or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. [less ▲]

Barrett's metaplasia, dysplasia and esophageal ademnocarcinoma: an inadequate antitumour immunity?

Conference (2012, February 09)

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis

in Journal of Proteome Research (2012)

The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface ... [more ▼]

The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface and in the extracellular space, establishing the first contacts with the target tissue. In this study, we had the rare opportunity to analyze a bone metastatic lesion and its corresponding breast primary tumor obtained simultaneously from the same patient. Using mass spectrometry, we undertook a proteomic study on cell surface and extracellular protein-enriched material. We provide a repertoire of significantly modulated proteins, some with yet unknown roles in the bone metastatic process as well as proteins notably involved in cancer cell invasiveness and in bone metabolism. The comparison of these clinical data with those previously obtained using a human osteotropic breast cancer cell line highlighted an overlapping group of proteins. Certain differentially expressed proteins are validated in the present study using immunohistochemistry on a retrospective collection of breast tumors and matched bone metastases. Our exclusive set of selected proteins supports the set-up of further investigations on both clinical samples and experimental bone metastasis models that will help to reveal the finely coordinated expression of proteins that favor the development of metastases in the bone microenvironment. [less ▲]

Proteomic kinetic analysis of blister fluid and serum in a patient with drug-induced toxic epidermal necrolysis. A comparison with skin immunohistochemistry.

in Current Drug Safety (2012), 7(5), 339-51

Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN ... [more ▼]

Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN pathobiology using a combination of immunohistochemistry and proteomics. Skin blister fluid (BF) and serum were collected in a patient in the early TEN stage at day (D) +4 of evolution and three days later (D +7). Intravenous cyclosporine A (CsA) treatment was initiated since D +4. Immunohistochemistry was performed on skin blister biopsies. In addition, proteomic analyses compared the BF protein content before and at the issue of the 3-day CsA treatment. Proteins were selected according to their prominent differential abundance in BF between D+4 and D+7, when influenced by lesional skin cells, but not in serum. Among 300 proteins, four were considered. Glutathione transferase pi was related to oxidative stress in TEN epidermis. The monocyte differentiation antigen CD14 and myeloperoxidase indicated macrophage activation. The proinflammatory S100-A8 protein probably originated from activated keratinocytes and/or macrophages. These proteomic findings were in line with immunohistochemistry and supported the prominent involvement of keratinocytes and macrophages in TEN pathomechanism. As opposed to CD14, other proteins were mainly present in BF at D+7, confirming that CsA expressed little effect, if any, on the activity of keratinocytes and macrophages in the present TEN patient. Of note, the present exploratory study using proteomic analyses in a single TEN case supports a pathogenic hypothesis without establishing any firm conclusion. [less ▲]

Toxic epidermal necrolysis and antifolate drugs in cancer chemotherapy.

in Current Drug Safety (2012), 7(5), 357-60

Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The ... [more ▼]

Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The latter cells lack the capacity to synthesize folates. In some patients, high dosages of antifolate drugs (eg: methotrexate, pemetrexed) used in cancer chemotherapy alter the keratinocytes, endothelial cells and Factor XIIIa+ dermal dendrocytes in a range of various severities. Such conditions clinically designed under the heading antifolate cytotoxic skin reaction (ACSR) occasionally resemble the toxic epidermal necrolysis (TEN) / Stevens-Johnson syndrome (SJS) spectrum. Whether or not the TEN/SJS presentation of ACSR is a regular condition similar to that induced by other drugs or a variant condition supported by a unique pathomechanism is unsettled. [less ▲]

Human papillomavirus DNA strongly correlates with a poorer prognosis in oral cavity carcinoma.

in Laryngoscope (2012), 122(7), 1558-65

OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV) in a clinical series of 162 patients with oral squamous cell carcinoma (OSCC) was studied. Furthermore, we analyzed the correlation ... [more ▼]

OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV) in a clinical series of 162 patients with oral squamous cell carcinoma (OSCC) was studied. Furthermore, we analyzed the correlation between the immunohistochemical expression of p16, p53, epidermal growth factor receptor (EGFR), and HPV status to predict survival in OSCC patients. STUDY DESIGN: Retrospective study. METHODS: Paraffin-embedded samples from OSCC patients (n = 162) were evaluated for the presence of HPV DNA using both GP5+/GP6+ consensus polymerase chain reaction (PCR) and type-specific E6/E7 PCR to detect HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, and 68. Immunohistochemical staining for p16, p53, and EGFR was also performed. RESULTS: The type-specific E6/E7 PCR demonstrated that 65 of the 147 OSCC patients (44%) presented with high-risk (hr) HPV types and that 38 of the 147 OSCC patients (26%) presented with low-risk (lr) HPV types. Comparable p53 and EGFR expression levels were observed in the hr HPV+ group (41.5% p53+, 92% EGFR+) and the lr HPV+ group (57% p53+, 92% EGFR+). Conversely, a slight increase in the proportion of p16+ tumors was observed in the hr HPV+ group (65%) compared with the lr HPV+ group (44%). In regard to patient outcome, the presence of HPV was correlated with a worse prognosis (P = .007). CONCLUSIONS: A high prevalence of hr and lr HPV infections was detected in the OSCC patients included in the study. Moreover, hr HPV positivity was correlated with a decreased 5-year disease-free survival rate compared with HPV- and lr HPV+. [less ▲]

Occurrence of cardiovascular calcifications in normal, aging rats.

in Experimental Gerontology (2012), 47(8), 614-9

BACKGROUND: Cardiovascular calcification is an independent predictor of morbidity and mortality and increases with age. Animal models are frequently used to investigate the underlying pathophysiology ... [more ▼]

BACKGROUND: Cardiovascular calcification is an independent predictor of morbidity and mortality and increases with age. Animal models are frequently used to investigate the underlying pathophysiology. Only scarce data regarding the effect of aging on calcifications in these animal models are available. The aim of this study is to investigate the occurrence of cardiovascular calcifications in normal, aging rats. METHODS: A mixed inbred/outbred population of 44 male Lewis/Wistar rats was studied. Group 1 of three-month-old rats, group 2 twelve-month-old, group 3 twenty-four-month-old and group 4 thirty-month-old rats. Calibrated integrated backscatter (cIB) values and blood parameters (creatinine, parathyroid hormone (PTH)) were measured, followed by ex-vivo micro-CT and histology as reference methods. RESULTS: Cardiovascular calcifications developed with age, as demonstrated by significantly increasing cIB values of the aortic valve and myocardium. This was confirmed by a significant increase in the calcified volume on ex-vivo micro-CT and in the histological calcium score. There was also a significantly higher level of creatinine and PTH with age. CONCLUSIONS: As in humans, cardiovascular calcifications progressively increase with age in the normal rat. Therefore the aging rat model could be used for studying calcifying cardiovascular disease. cIB might have a value in future studies for the early detection of subclinical calcifications in humans. [less ▲]