46 research outputs found
Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer
No full textData from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells "immune resistance," combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign "myeloid" cells, macrophages, and neutrophils, respectively. The development of cancer-specific "immune resistance" can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy
Variations of perceived exertion in relation to heart rate responses in an international level race walkers before a 50-km race
No full textIntroduction. The ability to accurately control and monitor exercise intensity (EI) during training sessions plays a key role in planning the athletic season. This can be achieved by means of rating of perceived exertion (RPE) (Borg, 1998) and heart rate (HR) (Achten and Jeukendrup, 2003). Over the years several RPE- and HR-based methods have been proposed to quantify global EI. However, to date no study has been conducted with regards to race walking (RW). Thus, this case study aimed to investigate the typical RPE and HR seasonal variations of an international level race walker training for a 50-km race and to examine the relationship between RPE and HR to further confirm the use of RPE to assess EI during RW-specific training. Methods. Training data were collected during the competitive season 2009 (127 training sessions) consisting of four macrocycles of intense training interspersed by one week of tapering before the Italian 50-km championship. The Borg’s 6-20 RPE scale (Borg, 1998) was used to measure the athlete perception of effort referred to the whole training session. HR was recorded using a short-range telemetry system and expressed relative to the maximum value (%HRmax) of the athlete determined during an incremental maximal test. The relationships between RPE and %HRmax were analysed using Pearson’s product moment correlation. Statistical significance was set at P < 0.05. Results. The athlete completed the event in 4h 14min 02s (personal best time, 39min 48s slower than the World Record). The mean RPE was 11.1 (1.6), 13.1 (1.3), 13.2 (1.5), 12.4 (1.3) and 11.4 (1.0), 13.5 (0.8), 12.7 (0.4), 12.0 (1.5) for the training and tapering period, respectively. The mean %HRmax was 83.7 (2.0), 85.3 (4.6), 84.8 (4.1), 85.7 (3.8) and 83.0 (0.7), 85.7 (4.5), 84.8 (1.6), 85.4 (2.5) % for the training and tapering period, respectively. The correlation between the mean RPE and %HRmax showed a very large significant relationship (r = 0.74, P = 0.04). Discussion. The result found indicates that a very large and significant relation exists between RPE and HR. This finding is in line with previous studies which showed how RPE is correlated with many physiological variables, such as HR (Chen et al., 2002), and provides evidence which confirms that RPE can be considered a simple and valid method for quantifying the global EI during RW-specific training. References Achten J, Jeukendrup AE. (2003). Sports Med, 33, 517-538 Borg G. (1998). Borg’s perceived exertion and pain scale. Human Kinetics, Champaign, IL Chen MJ, Fan X, Moe ST (2002). J Sports Sci, 20, 873-899
Aberrant BLM cytoplasmic expressionassociates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer
No full textBackground Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 30–50 DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood. Methods The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay.
Results In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapsefree survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and cH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan. Conclusions Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients
Specific expression patterns of epithelial to mesenchymal transition factors in gestational molar disease
No full textThe epithelial to mesenchymal transition, a well-known and re-emerging model in pathology, has not been completely investigated in the field of gestational pathology. This study aims at improving the comprehension of this process in molar disease, even looking for new possible immunohistochemical markers.
We have analysed the immunohistochemical expression of Twist1 and Snai2, two of the most important transcription factors involved in epithelial to mesenchymal transition, in formalin-fixed paraffin-embedded samples of 23 spontaneous abortive pregnancies, 22 molar pregnancies (10 partial and 12 complete) and 7 term placentas.
Twist1 and Snai2 were highly expressed in stromal villi cells of molar disease. Particularly, Twist1 was highly expressed in complete moles compared to both abortive pregnancies (p < 0.001) and partial moles (p < 0.05). Also Snai2 was more expressed by complete moles, differentiating them from non-molar abortions (p < 0.05).
On the basis of the known cadherins and claudins expression in these pathologies, our new findings reinforce the hypothesis of the involvement of epithelial to mesenchymal transition in early molar pregnancies and above all in complete moles. Furthermore, we highlighted that in molar disease not only the trophoblast, but even the villi stromal cells, are involved. Thanks to their specificity, furthermore, these Twist1 and Snai2 could be used as additional immunohistochemical tool in the diagnosis of complete molar disease, with Twist1 as the first choice
CROC-Mutated rhabdoid colorectal carcinoma showing in intracellular spaces lamellipodia and cellular projectionts revealed by electron microscopy
No full textAbstract Background Rhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell. Methods Here, we investigated two cases of CROCCmutSMARCB1wt RC by scanning and transmission electron microscopy (SEM, TEM). Results TEM confirmedthediagnosticpresenceofintermediatecytoplasmicfilamentsandnucleolarmargination.SEM showed cellular protrusions (lamellipodia) in the intercellular spaces not evident at light microscopy. Conclusions TheseprotrusionsCROCC-relatedmightrepresentthepathogeneticmechanismunderlyingtherhabdoidaggressive behavior, independently of tumor staging. To our knowledge, the SEM technique was applied in the study of this neoplasm for the first time
Emerging insight into MAPK inhibitors and immunotherapy in colorectal cancer
No full textOur understanding of the genetic and non-genetic molecular alterations associated with colorectal cancer (CRC) progression and therapy resistance has markedly expanded in the recent years. In addition to their effects on tumor biology, targeted therapies can have effects on host immune responses. However, the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity need to be comprehensively defined. There is good evidence in the literature that alterations in different members of the MAPK superfamily (mainly ERKs and p38 MAPKs) modify the inflammatory response and antitumor immunity, enhancing metastatic features of the tumors. In addition, a plethora of alterations that emerge at relapse often converge on the activation of MAPKs, particularly, ERKs, which act in concert with other oncogenic signals to modulate cellular homeostasis and clonal evolution during targeted therapies. Herein, we discuss how this knowledge can be translated into drug development strategies aimed at increasing tumor antigenicity and antitumor immune responses. Insights from these studies could provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of CRC
Crosstalk between the tumor microenvironment and immune system in pancreatic ductal adenocarcinoma: Potential targets for new therapeutic approaches
No full textPancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials
Nano albumin bound-paclitaxel in pancreatic cancer: Current evidences and future directions
No full textPancreatic cancer (PDAC) is an aggressive and chemoresistant disease, representing the fourth cause of cancer related deaths in western countries. Majority of patients have unresectable, locally advanced or metastatic disease at time of diagnosis and the 5-year survival rate in these conditions is extremely low. For more than a decade gemcitabine has been the cornerstone of metastatic PDAC treatment, although survival benefit was very poor. PDAC cells are surrounded by an intense desmoplastic reaction that may create a barrier to the drugs penetration within the tumor. Recently PDAC stroma has been addressed as a potential therapeutic target. Nano albumin bound (Nab)-paclitaxel is an innovative molecule depleting tumor stroma, through interaction between albumin and secreted protein acidic and rich in cysteine. Addition of nab-paclitaxel to gemcitabine has showed activity and efficacy in metastatic PDAC first-line treatment improving survival and overall response rate vs gemcitabine alone in the MPACT phase III study. This combination represents one of the standards of care in advanced PDAC therapy and is suitable to a broader spectrum of patients compared to other schedules. Nab-paclitaxel is under investigation as a backbone of chemotherapy in novel combinations with target agents or immunotherapy in locally advanced or metastatic PDAC. In this article, we provide an updated and critical overview about the role of nab-paclitaxel in PDAC treatment based on the latest advances in preclinical and clinical research. Furthermore, we focus on the use of nab-paclitaxel within the context of metastatic PDAC treatment landscape and we discuss about future implications in the light of current clinical ongoing trials
CROCC-mutated rhabdoid colorectal carcinoma showing in intercellular spaces lamellipodia and cellular projections revealed by electron microscopy
No full textRhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell
Wnt (canonical and non canonical) pathways in breast carcinoma with extensive vascular invasion and inflammatory breast carcinoma
No full textBACKGROUND: Breast carcinoma with extensive peritumoral vascular invasion (ePVI-BC) is a cancer with massive vascular invasion (>10) detected in more than one slide. This neoplasm shows clinic-pathological affinity with inflammatory breast carcinoma (IBC). In this paper we evaluate their biological relationship through the study of surrogate markers (beta-catenin and NFAT5) of Canonical (cWnt) and non-canonical (nWnt) Wnt pathways activation.METHODS: By immunoistochemistry, we investigate beta-catenin and NFAT5 in 39 IBC, 74 ePVI-BC and 84 control cases (CG-BC).RESULTS: cWnt was activated in 100 % of ePVI-BC, in 64 % of IBC and 10 % of CG-BC. nWnt was activated in 20 % of ePVI-BC, 50 % of IBC and 1% of CG-BC. The prognosis of carcinomas with nWnt activated was poor similar to IBC. The statistical analysis evidences as both the pathways are synergistic in malignant progression and survival time. beta-catenin show an important association with prognostic factors and NFAT5 shows a relevant prognostic role on OS (p = 1.5*10-6) and DFS (P = 1,2*10-4). nWnt is associated with a worse prognosis independently of cWnt. cWnt is associated with adverse prognosis (DFS p = 0.0469; OS p = 0.004891) but its prognostic role is indifferent in carcinoma with nWnt activated.CONCLUSIONS: Canonical Wnt pathway is involved in malignant progression with dominant role for vascular invasion whereas non canonical Wnt pathway plays an important role on survival time including the capacity to identify carcinomas with IBC-like prognosis. Furthermore ePVI may represent a "prodromal form of IBC" as demonstrated by its clinicopathological and biological similarity with IBC
