Changes In Malignant Cells Research Articles

Glycan changes: cancer metastasis and anti-cancer vaccines

Complex carbohydrates, which are major components of the cell membrane, perform important functions in cell-cell and cell-extracellular matrix interactions, as well as in signal transduction. They comprise three kinds of biomolecules: glycoproteins, proteoglycans and glycosphingolipids. Recent studies have also shown that glycan changes in malignant cells take a variety of forms and mediate key pathophysiological events during the various stages of tumour progression. Glycosylation changes are universal hallmarks of malignant transformation and tumour progression in human cancer, which take place on the whole cells or some specific molecules. Accordingly, those changes make them prominent candidates for cancer biomarkers in the meantime. This review mainly focuses on the correlation between glycosylation and the metastasis potential of tumour cells from comprehensive aspects to further address the vital roles of glycans in oncogenesising. Moreover, utilizing these glycosylation changes to ward off tumour metastasis by means of anti-adhesion approach or devising anti-cancer vaccine is one of promising targets of future study.

Radiology contributes to better cytological diagnosis of lung tumors

Objectives Cytology is well established and widely accepted method to diagnose lung tumors. However, cytological changes of malignant cells can be so subtle that cytopathologists cannot always diagnose with certainty. In such cases, some cytopathologists believe that radiological assessment is important for correct cytological diagnosis. However others deny the importance of radiological information, because they believe it could not change the cytological assessment. This study mainly aimed to clarify how radiologist's comments affect cytological diagnosis of lung tumors. Methods Of 201 patients who underwent cytological examinations, 131 and 57 patients were diagnosed with malignant and benign lung lesions, respectively. Study coordinators randomly selected 60 cytological slides each of the benign and malignant lesions. A radiologist graded their CT images by using a 5-point confidence scale. Three cytotechnologists assessed the 120 cytological slides twice on the basis of a 5-grade classification: first before and then after obtaining radiologist's grading. Receiver operating characteristic analysis was performed. The Az values, sensitivities, and specificities of the cytological diagnoses were calculated for comparing the results before and after obtaining radiologist's grading. Results The mean Az value for cytological assessment after obtaining radiologist's grading (0.88) was significantly higher than that before obtaining radiologist's grading (0.78). The mean sensitivity of cytological assessment after obtaining radiologist's grading (77%) was significantly higher than that before obtaining radiologist's grading (67%). Conclusions Radiological assessment, together with a radiologist's confidence, improves cytological diagnoses of lung diseases. Thus, the importance to positively provide radiological assessment to cytopathologists should be considered by all clinicians.

Clinical Significance of FDG Single-Photon Emission Computed Tomography: Computed Tomography in the Diagnosis of Head and Neck Cancers and Study of Its Mechanism

The metabolic changes of malignant cells are earlier than these of morphology. (18)F-fluorodeoxyglucose (FDG) single-photon emission computed tomography (SPECT)-computed tomography (CT) systems provide functional and anatomic images that could significantly improve its diagnostic capability. The molecular mechanisms of increased FDG uptake are still not fully understood. The correlation between FDG uptake and the expression of Glut in various tumor cells is still under debate. Further study is necessary to correlate increased FDG uptake by tumors with their Glut-1 and Glut-3 expression, which will lead to a better understanding and interpretation of SPECT-CT imaging. In this study, we, therefore, investigated in patients with head and neck carcinoma (HNC) the relationship between tumor FDG accumulation and the mRNA expression and protein expression of Glut-1 and Glut-3. Overall, 25 patients with HNC who underwent SPECT-CT imaging and CT or magnetic resonance imaging (MRI) studies were performed between April 2002 and March 2004. Then, the mRNA and protein expression of Glut-1 and Glut-3 in these 25 surgical or biopsied samples were studied with HNC to determine the correlate increased FDG uptake by tumors with their Glut-1 and Glut-3 expression. Visual analysis of (18)F-FDG SPECT-CT gave sensitivity, specificity, and accuracy levels of 100%, 62.5%, and 88%, respectively. The tumor-to-background (T/B) ratios were 94.1%, 87.5%, and 92.0% for (18)F-FDG SPECT/CT, and 64.7%, 50.0%, and 60.0% for CT and MRI. This indicates that (18)F-FDG SPECT-CT is superior to CT and MRI. Significant correlation was found between FDG and Glut-1 mRNA or Glut-1 protein (p < 0.001). There was no correlation between T/B ratio and Glut-3 mRNA (r = 0.14, p > 0.01). (18)F-FDG SPECT-CT can be as a prospective tool that can judge the malignancy or benignity of head and neck tumor, stage and classify the tumor, distinguish recurrence or necrosis or fibrosis of the tumor after treatment by surgery or radiotherapy, and detect unknown primary tumor. Glut-1 may largely mediate basal glucose transport in HNC cells.

HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

Changes in classical and nonclassical HLA class I as well as HLA class II antigens have been identified in malignant lesions. These changes, which are described in this review are believed to play a major role in the clinical course of the disease since both HLA class I and class II antigens are critical to the interaction between tumor cells and components of both innate and adaptive immune system. Abnormalities in HLA antigen expression in malignant cells, which range in frequency from 0-90%, are caused by distinct mechanisms. They include defects in beta(2)-microglobulin (beta(2)m) synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations, which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms, which control HLA antigen expression and/or abnormalities in one or more of the antigen processing, machinery (APM) components. More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, APM component, costimulatory molecule and tumor antigen (TA) expression in malignant cells. The types of epigenetic modifications that may occur in normal and malignant cells as well as their role in changes in HLA antigen expression by malignant cells have been reviewed. The epigenetic events associated with alterations in HLA antigen expression may be clinically relevant as, in some cases, they have been shown to impair the recognition of tumor cells by components of the adaptive immune system. The functional relevance and potential clinical significance of these epigenetic alterations have been addressed. Finally, unlike genetic alterations, epigenetic modifications can, in some cases, be reversed with pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation. Therefore, strategies to overcome epigenetic modifications underlying changes in HLA antigen expression in malignant cells have been discussed.

Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent

The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redox-silence is a prerequisite property for most of the anticancer activities described in this communication.

Intra-Lineage Phenotypic Switch in T-Cell Prolymphocytic Leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell disorder characterized by an aggressive clinical course and short survival. Immunophenotypically, the leukemic cells show heterogeneous CD4 and CD8 expression; most cases are CD4+CD8− but, CD4+CD8+ and CD4−CD8+ cases are recognized. CD4+CD8+ phenotype is conventionally associated with cortical thymocytes, however, double positive T-prolymphocytes, are TdT −, CD1a − and CD3+ suggesting a post-thymic origin. Phenotypic changes in malignant cells while recognized in acute leukemias, are rare in mature T-cell disorders. In T-PLL, there is only 1 report describing 2 cases of phenotypic change (Tuset et al, Leukemia and Lymphoma 2001.42:1379-83). We retrospectively investigate the frequency of this phenomenon amongst 20 patients with T-PLL for whom sequential immunophenotyping of leukemic cells was available. This included the 2 cases previously reported. Diagnosis of T-PLL was based on clinical features, morphology, immunophenotype and karyotype. Membrane markers were sequentially evaluated by flow cytometry on peripheral blood and bone marrow. Sequential chromosome analysis of metaphases derived from T-mitogen stimulated metaphases cultures was available in a proportion of cases. Intra-lineage phenotypic switch occurred at relapse in 5 cases (25%) (table 1). No characteristic pattern of switch was seen. Serial karyoptying was available in 3 of these 5 patients (60%) and showed acquisition of additional cytogenetic abnormalities at the time of relapse. Change in morphology was documented in 1 case where cells displayed a more ‘blastic' appearance with loss of CD52. Change in phenotype was mirrored in clinical features with increasingly progressive disease and refractoriness to treatment. In all cases, a mature TdT negative phenotype was maintained. Splenectomy was not performed in the interval between initial and documented change in phenotype and LGL's were not apparent morphologically or by flow cytometry in these 5 patientsChange in phenotype in T-PLLSubsequent phenotypeInitial phenotypeCD4+CD8−CD4+CD8+CD4−CD8+TotalCD4+CD8−81*09 (45%)CD4+CD8+022*4 (20%)CD4−CD8+1*1*57 (35%)Total9 (45%)4 (20%)7 (35%)20* change in phenotype. All patients received alemtuzumab treatment and while it is possible that this agent selectively depleted sub-clones of the disease, the lack of a consistent emergent phenotype, together with acquisition of additional cytogenetic abnormalities as opposed to replacement by a different abnormal karyotype, favors clonal evolution as a likely cause. Such change in phenotype was not observed in the remaining 15 patients despite alemtuzumab treatment in the majority. Our findings indicate that intra-lineage phenotypic switch in T-PLL occurs in up to 25% of cases. This indicates the need to use comprehensive T-cell panels in monitoring for minimal residual disease and/or relapse. Sequential evaluation of phenotype and cytogenetics may provide valuable insights into mechanisms of relapse and resistance and may impact on treatment selection in T-PLL.

Historical prospective of human cytogenetics: from microscope to microarray

After the fundamental discovery in 1956 that normal human cells contain 46 chromosomes, clinical cytogenetics was born and studies into the relation of chromosomal defects and disease could begin. Although many technical advances have been made over this long period, including the introduction of molecular techniques, until now, all cytogenetic studies have been performed through regular microscopes, which was throughout the years the most important equipment of a cytogenetic laboratory. However, recently a new technique has been introduced based on comparative genomic hybridization on an array of thousands of different probes (array-CGH). This technique enables an increase in the sensitivity of detecting chromosomal aberrations far beyond the detection limit of regular banding techniques. Furthermore, it gives us the possibility to detect genomic changes in malignant cells in cases where aberrations are too complex to study or when chromosomes are not available at all. Cytogenetic laboratories are now challenged to introduce and incorporate this new application next to the various well-established microscopical techniques to provide optimal diagnostic services.

Nucleolus and apoptosis.

The nucleolus represents a highly dynamic nuclear compartment of the interphase nucleus. It plays a key role in ribosome biogenesis. The number of nucleoli, their size, and their activity increase in exponentially growing cells; therefore these parameters reflect the proliferating activity of the cells. A variety of staining techniques have been employed to vizualize nucleolar changes in malignant cells. Staining of so-called nucleolar organizer regions (NORs), based upon a strong avidity of nucleolar proteins to bind silver ions, represents the technique most frequently used by pathologists. Nucleolar changes and pleomorphism associated with overt proliferation of tumor cells have also been documented by immunohistochemical and ultrastructural studies. Contrary to cell proliferation, cytostatics-induced changes of nucleolar phenotype in malignant cells point to a potential role of nucleolar components in the execution of active cell death. Recent studies have provided direct clues that so-called death domains and other apoptosis-related proteins are accumulated in nucleoli upon induction of active cell death. It can be concluded that the plurifunctionality of nucleoli regarding cell proliferation and apoptosis could open new vistas toward understanding dysregulation in malignant cells.

Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy.

Treatment regimens for advanced squamous cell carcinoma of the head and neck require both attention to local tumor burden as well as contingencies for control of disseminated disease. Relatively new protocols utilizing cisplatin for radiosensitization of tumor cells during concomitant radiotherapy have shown progress in providing effective tumor control. Cisplatin as a chemotherapeutic agent induces DNA changes in malignant cells that may be mutagenic or lethal. Additionally, when used concurrently with radiation therapy, cisplatin acts as a radiosensitizer, increasing damage to malignant nuclear DNA to enhance the anti-neoplastic capability of radiotherapy. The mechanisms by which this radiosensitization occurs remain controversial, although one leading theory involves cisplatin's ability to inhibit sublethal damage repair in radiated tumor cells. Recent investigations utilizing cisplatin with concurrent radiation for treatment of advanced squamous cell carcinomas of the head and neck are reviewed. The variations in protocols presented include route of administration, dosing, scheduling, timing with surgery, and combination therapy with 5-fluorouracil and radiation. Higher response rates, prolonged mean survival, increased survival rates, longer local recurrence-free survival rates, and considerable organ preservation with the use of concurrent cisplatin and radiation have been demonstrated by these studies. Further investigation of concurrent cisplatin and radiotherapy in patients with advanced disease is justified.

Stem cells in breast epithelia.

The rodent and human nonpregnant mammary glands contain epithelial, intermediate and myoepithelial cells which have all been isolated as cell lines in vitro. Transforming growth factor-alpha (TGF alpha) and basic fibroblast growth factor (bFGF) are produced by myoepithelial cells and can stimulate the growth of intermediate stem cells in vitro. Epithelial and intermediate cells behave like stem cells in vitro, since they can differentiate into alveolar-like an myoepithelial cells. The myoepithelial differentiation pathway is associated with the early expression of a calcium-binding regulatory protein called p9Ka and the protease, Cathepsin D. Myoepithelial cells are also present in benign lesions but not in malignant mammary carcinomas of rats or humans, whose resultant cell lines fail to differentiate completely along the myoepithelial cell pathway. Loss of the myoepithelial cell in some invasive carcinomas may be compensated, at least in part, by changes in malignant cells. Over-expression of TGF alpha and/or erbB receptors may reduce the requirement for TGF alpha, whilst ectopic production of bFGF and its receptors and p9Ka/Cathespin D may assist in tumorigenesis and in metastasis, respectively. Thus compensation for, or retention of, molecules potentially involved in the differentiation of mammary cells may be a mechanism by which malignancy progresses in some human invasive carcinomas.

Sequential cytopunctures during preoperative chemotherapy for primary breast carcinoma. Cytomorphologic changes, initial tumor ploidy, and tumor regression

Thirty-five patients with large but operable breast carcinoma (T3, N0-N1, M0) received before surgery three cycles of preoperative Adriamycin (doxorubicin), vincristine, cyclophosphamide, methotrexate, 5-fluorouracil (AVCMF) chemotherapy (CT). All patients had sequential cytopunctures for both cytologic examination and flow cytometric DNA analysis (FCM): one before treatment and the three others after each cycle of CT. At cytologic examination, 20 carcinomas showed CT-induced cytomorphologic changes. These changes in malignant cells were also evaluated on histologic sections after surgery. A significant relationship was found between cytomorphologic changes in cytopunctures and in the corresponding tumor tissue. The lobular carcinomas did not reveal changes either on cytologic or on histologic study. At FCM analysis before treatment, ten carcinomas were diploid and 25 were nondiploid. When initial tumor ploidy was compared to cytomorphologic changes, none of the diploid carcinomas showed changes. An objective tumor regression was observed in 12 of 20 tumors with cytomorphologic changes and in four of 15 tumors without changes on cytologic examination. But, a significant relationship appeared only when cellular changes were evaluated on histologic analysis. When tumor regression was compared to ploidy before treatment, the rate of objective regression was significantly higher in nondiploid tumors (15/25) than in diploid tumors (one of ten). From these findings, initial tumor diploidy could be a predictor of tumor chemoresistance, whereas cytomorphologic changes during chemotherapy could be an indicator of tumor cell chemosensitivity.

Hyperthermia and microcirculatory effects of heat in animal tumors.

Up to the present, much attention in cancer research has been focussed on biological changes of malignant cells in vitro when they are treated with hyperthermia. Very little is known how and to what extent the in vivo environment in which these cells are lodged will affect the therapeutic outcome. As a consequence of functional as well as morphological differences of microvascular beds in neoplastic tissue, attempts were made recently to exploit the possibility of enhancing the efficacy of tumor therapy by affecting the microcirculation. Some encouraging results were obtained, and the combination of hyperthermia and conventional tumor treatment began to attract an increasing number of investigators because nutritionally deprived and hypoxic tumor cells appeared to be particularly sensitive to heat (Overgaard and Bichel 1977; Overgaard and Nielsen 1980; Overgaard 1981; Rhee 1984; for a review see Streffer 1985; Vaupel et al. 1983). The extent and etiology of vascular damage in tumors and the possible clinical impact are still subjects of controversy. It is the aim of this paper to: 1. Describe the typical features of a tumor microcirculation as reported in the literature 2. Summarize the changes occurring in the tumor microcirculation as a result of hyperthermia 3. Discuss the mechanism(s) involved in vascular damage KeywordsWall TensionTumor Blood FlowCapillary Blood FlowAmelanotic MelanomaTumor TemperatureThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Aprotinin induces surface changes in malignant cells in culture: a possible mode of antitumour action.

Treatment of TRES cells with aprotinin (Trasylol) produced marked changes in their surface properties. There was a concentration-dependent increase in the surface charge density of the cells. The agglutinability of the cells was inhibited by the antiproteinase. The cells became less adhesive to concanavalin A-linked plates. The adhesion of treated TRES cells appeared to be mediated by lectin receptors with lower specificity for concanavalin A. These observations and an analysis of the kinetics of adhesion have suggested the possibility that a new class of concanavalin A receptors appears on the surface of aprotinin-treated TRES cells, which might increase immunogenicity of the cells.