激活转录因子2及其在肿瘤中的研究进展

激活转录因子2(ATF2)主要通过介导细胞感受外界刺激而调节转录.多项研究显示ATF2参与恶性肿瘤的发生及肿瘤细胞的增殖、分化、凋亡、侵袭及转移等过程的调节.ATF2的激活可促进肿瘤细胞生长,但也有部分报道显示ATF2的激活可抑制肿瘤细胞生长.进一步揭示ATF2在各种肿瘤形成过程中的作用机制,可为肿瘤的病因学研究和治疗学探索提供新的思路.     

Nuclear localization of apoptosis protease activating factor-1 predicts survival after tumor resection in early-stage non-small cell lung cancer.

The proapoptotic protein apoptosis protein activating factor-1 (Apaf-1), which is normally located in the cytoplasm, can translocate to the nucleus before non-small cell lung carcinoma (NSCLC) cells manifest signs of apoptosis such as mitochondrial damage, caspase activation, or chromatin condensation. This may indicate a stage of imminent apoptosis. Importantly, we found that 24% (15 of 62) of resected stage I NSCLC (T(1)N(0)M(0) or T(2)N(0)M(0)), manifested a marked nuclear localization of Apaf-1 (Apaf-1(Nuc)), as compared with the mostly cytoplasmic localization of Apaf-1 found in the remaining tumors (Apaf-1(Cyt)). After a median follow-up of 6.31 years, the actuarial 5-year overall survival rates were 89% (56-98%) in the Apaf-1(Nuc) group and 54% (36-71%) in the Apaf-1(Cyt) group (P = 0.039). No correlation between the subcellular localization of Apaf-1 and that of p53 and Hsp70 could be established. Thus, the subcellular location of Apaf-1 (but not that of p53 or Hsp70) constitutes an accurate prognostic factor for overall survival in NSCLC.     

小眼畸形相关转录因子在黑色素瘤转移中的作用

小眼畸形相关转录因子(MITF)一直是近几年黑色素瘤细胞研究中的热点.异常表达的MITF与黑色素瘤的发生和转移密切相关,且MITF低表达能促进黑色素瘤细胞的侵袭.研究MITF及与其相关的分子和信号通路的调节关系,将进一步加深对恶性黑色素瘤转移分子机制的理解,为开发新的分子靶向药物提供帮助.     

The activation-associated antigen 4F2 predicts patient survival in low-grade B-cell lymphomas

Expression of the activation-associated 4F2 antigen, transferrin receptor and interleukin-2 (IL-2) receptor on suspended cells from 75 biopsied low-grade non-Hodgkin lymphomas (L-NHL) of B-cell origin was correlated to patient survival, clinical prognostic parameters and estimated DNA synthesis. 4F2 antigen expression correlated significantly with poor patient survival, high DNA synthesis and transferrin receptor expression. Transferrin receptor expression was associated with high DNA synthesis and treatment response, but not with patient survival. On the other hand, IL-2 receptor was correlated neither to patient survival nor to other studied markers for cell activation, but seemed to be expressed on certain subsets of lymphomas. We suggest that monoclonal antibody (MAb) against the activation-associated 4F2 antigen could be used to select patients with L-NHL for aggressive chemotherapy.     

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients

BackgroundThe outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methodsctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).ResultsThe detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.ConclusionPre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.     

Tumor iNOS predicts poor survival for stage III melanoma patients

Inducible nitric oxide synthase (iNOS) produces nitric oxide, which has growth promoting activity in melanoma. A preliminary study of tumors from patients with Stage III melanoma who had received neo-adjuvant therapy revealed an association of tumor iNOS expression with shortened survival. The objective of the present study was to determine whether iNOS expression in tumors of newly diagnosed, untreated Stage III patients is predictive of survival. iNOS expression was examined by immunohistochemistry in tumors from 132 patients. The staining was evaluated for percentage of positive cells (Number score) and the intensity of staining (Intensity score). The association of iNOS expression with overall and disease-specific survival was tested in univariate and multivariate Cox proportional hazards regression models that included other known prognostic factors. Results of the univariate analysis demonstrated that the presence of iNOS in a patient's tumor, whether graded on the basis of Number or Intensity score, was associated with a significant increase in the hazard ratio of death from melanoma. These findings were corroborated by median survival data estimated from Kaplan Meier analysis. In the multivariate model including iNOS number or intensity, gender, age, number of lymph nodes, macroscopic disease and in-transit disease, only iNOS expression predicted survival. We conclude that a significant association exists between tumor iNOS expression and shortened survival in untreated Stage III melanoma patients. The ability of iNOS to predict outcomes for these patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility.     

Lymph node ratio predicts disease‐specific survival in melanoma patients

BACKGROUND:

The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease‐specific survival (DSS) outcomes in patients with melanoma.

METHODS:

Patients with lymph node‐positive melanoma who underwent therapeutic LN dissection of the neck, axilla, and inguinal region were identified from the SEER database (1988‐2005). We performed Cox multivariate analyses to determine the impact of the total number of LNs removed, number of negative LNs removed, and LN ratio on DSS. Multivariate cut‐point analyses were conducted for each anatomic region to identify the threshold values associated with the largest improvement in DSS.

RESULTS:

The LN ratio was significantly associated with DSS for all LN regions. The LN ratio thresholds resulting in the greatest difference in 5‐year DSS were .07, .13, and .18 for neck, axillary, and inguinal regions, respectively, corresponding to 15, 8, and 6 LNs removed per positive lymph node. After adjustment for other clinicopathologic factors, the hazard ratios (HRs) were .53 (95% confidence interval [CI], .40 to .71) in the neck, .52 (95% CI, .42 to .65) in the axillary, and .47 (95% CI, .36 to .61) in the inguinal regions for patients who met the LN ratio threshold.

CONCLUSIONS:

Among the prognostic factors examined, LN ratio was the best indicator of the extent of LN dissection, regardless of anatomic nodal region. These data provide evidence‐based guidelines for defining adequate LN dissections in melanoma patients. Cancer 2009. © 2009 American Cancer Society.     

Subcellular localization of basic fibroblast growth factor and fibroblast growth factor receptor 1 in pituitary adenomas

The aim of this study was to assess the subcellular localization of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor 1 (FGFR1) in pituitary adenomas. We studied 61 patients who had primary pituitary adenomas and underwent operation. The immunohistochemistry for bFGF, FGFR1, and MIB-1 was examined in paraffin-embedded tissues. The bFGF immunoreactivity in the nucleus was recorded as the bFGF nuclear index, which was calculated as the percentage of tumor cells with the bFGF immunoreactivity in the nuclei when more than 1000 tumor cells were examined. Recurrent adenomas were found in 7 patients during follow-up periods ranging from 8 to 134 months (mean, 57.2). The recurrent adenomas had significantly larger mean bFGF nuclear indices (74.8±28.8%) than the nonrecurrent adenomas (25.4±32.1%,P=0.0003). The bFGF nuclear index also correlated significantly with the maximum tumor diameters and the invasiveness to the cavernous sinuses (Knosp grade) in the adenomas. The cytoplasmic FGFR1 immunoreactivity was inversely correlated (P<0.02) with maximum tumor diameter. Neither cytoplasmic bFGF, cytoplasmic FGFR1, nor MIB-1 staining index showed any relationship with the recurrence of pituitary adenomas. These findings suggest that the nuclear accumulation of bFGF plays an important role in the progression of pituitary adenomas without its receptors.     

Subcellular localization, redistribution and photobleaching of sulfonated aluminum phthalocyanines in a human melanoma cell line

Intracellular localization, intracellular translocation and photobleaching following non-lethal laser microirradiation of the fluorescing derivatives of sulfonated aluminum phthalocyanines (Al-PcSn, n = 1-4) in a human melanoma cell line (LOX) were studied by means of confocal laser scanning microscopy (LSM) and image processing. Use of confocal microscopy allowed 3-dimensional information to be obtained. Both Al-PcS1 and Al-PcS2 localized diffusely in the cytoplasm of the cells, while Al-PcS3 and Al-PcS4 exhibited a granular pattern in the extranuclear fraction of the cells. None of the Al-PcSn family was observed in the nuclei of the cells except that a small fraction of fluorescence was occasionally detected in nuclei of some cells treated with Al-PcS1 and Al-PcS2. Furthermore, exactly the same granular localization patterns and positions in the same cells were found after incubation initially with Al-PcS3 (or Al-PcS4) followed by acridine orange (AO) which emits red fluorescence from lysosomes of cells. Thus, the granular fluorescence of Al-PcS3 and Al-PcS4 is confined to the lysosomes of the LOX cells. Non-lethal laser exposure of cells incubated with high concentrations of the 2 dyes resulted in a translocation of the dyes from the lysosomes to the whole cytoplasm and an increase in total intracellular fluorescence intensity. Finally, a small fraction of the dyes localized into the nuclei of the cells. The laser exposure of cells incubated with low concentrations of the lysosomally localized dyes resulted in an increase in the intracellular fluorescence intensity with no translocation of the dyes. Under all conditions, high laser exposure resulted in a decrease in the total intracellular fluorescence intensity.     

Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival

BACKGROUND: The impact of mononuclear cell infiltration on renal cell carcinoma (RCC) biology has been controversial, previously reported to be associated with either a favorable or unfavorable prognosis. The objective of the current study was to evaluate associations between mononuclear cell infiltration in routinely prepared paraffin-embedded specimens with survival in patients with clear-cell RCC. METHODS: A total of 306 patients were identified treated with nephrectomy for clear-cell RCC between 1990 and 1994. A single urologic pathologist, blinded to patient outcome, reviewed the specimens and quantified the extent of mononuclear cell infiltration as absent, focal, moderate, or marked. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of mononuclear cell infiltration with death from RCC were assessed using Cox proportional hazards regression models. RESULTS: At last follow-up, 173 of the 306 patients studied had died, including 96 patients who died from RCC. Mononuclear cell infiltration was absent in 165 (54%), focal in 70 (23%), moderate in 53 (17%), and marked in 18 (6%). Univariately, patients with specimens that had mononuclear cell infiltration were over 2 times more likely to die from RCC compared with patients whose specimens exhibited no mononuclear cell infiltration (risk ratio, 2.63; P < .001). After adjusting for the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score, patients with specimens that had mononuclear cell infiltration exhibited a significantly increased likelihood of dying from RCC compared with patients whose specimens had no mononuclear cell infiltration (risk ratio, 1.61; P = .028). CONCLUSIONS: Mononuclear cell infiltration is associated with death from RCC even after multivariate adjustment. Routine documentation of mononuclear cell infiltration is recommended during the pathologic assessment of RCC.     

Cyclooxygenase-2 expression predicts survival in malignant pleural mesothelioma

The expression of cyclooxygenase 2 (COX-2) protein is increased in many tumours and may be associated with a more aggressive phenotype. We aimed to assess COX-2 expression in a large series of archival mesothelioma specimens. Archival tissue was obtained from 86 malignant pleural mesothelioma samples (histological subtype: 42 epithelial, 28 biphasic and 16 sarcomatoid). Overexpression of COX-2 was detected by immunohistochemical analysis. Positive staining was located in the cytoplasm of malignant tumour cells. Overall 51/86 (59%) tumour sections demonstrated COX-2 overexpression. The frequency varied with histological subtype with 31/42 (73%) of epithelial sections, 14/28 (50%) of biphasic sections and 6/16 (37%) of sarcomatoid sections recorded as positive. Kaplan Meier survival analysis indicated that overexpression of COX-2 was significantly related to improved prognosis (P < 0.001) and was an independent prognostic factor in multivariant analysis. Overexpression of COX-2 protein may confer a survival advantage in mesothelioma patients.