基于小鼠肥大细胞瘤P815模型的肿瘤免疫学研究进展

肿瘤动物模型是研究肿瘤免疫学、临床前期评价肿瘤治疗方案有效性和安全性的重要前提.P815肿瘤模型是一种较为成熟的小鼠肿瘤研究模型,因其具有某些独特的优点而被研究者广泛采用.近年来,在已鉴定出P815AB、P815E等肿瘤抗原的基础上,基于该模型的肿瘤疫苗及相关肿瘤免疫学研究都有了相当大的进展.     

The pros and cons of chemokines in tumor immunology

Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune-mediated rejection of cancer.     

Cyclooxygenase-2 and thromboxane synthase in non-endocrine and endocrine tumors: A review

Prostaglandins (PG) are members of a large group of hormonally active fatty acids derived from free fatty acids. They are formed from arachidonic acid—the major PG precursor. Cyclooxygenase (COX)-1 and -2 are the rate-limiting steps in PG synthesis. COX-2 is overexpressed in many human non-endocrine and endocrine tumors including colon, breast, prostate, brain, thyroid, and pituitary. COX-2 has an important role in angiogenesis and tumor growth. Thromboxane synthase (TS) catalyzes the synthesis of thromboxane A2 (TXA2), which is derived from arachidonic acid and prostaglandin H₂ and is a vasoconstrictor and inducer of platelet aggregation. TXA2 stimulates tumor growth and spread of some tumors and TS appears to have a critical role in tumorigenesis in some organ systems. In this review, we examine the role of COX-2 and TS in various non-endocrine tumors, especially colon, breast, prostate, and brain as well as in endocrine tumors. The accumulating evidence points to an increasingly important role of COX-2 and TS in tumor progression and metastasis.     

肿瘤疫苗的研究现状

肿瘤在体内的排斥/控制主要依赖于肿瘤抗原特异性T淋巴细胞.T淋巴细胞通过TCR与肿瘤细胞表面表达的HLA-抗原肽复合物的相互作用来识别其靶分子.与特异性HLA-抗原肽复合物有价值的相互作用诱导了淋巴细胞克隆的扩增以及一系列的免疫反应.目前,从理论上已经提出了以整个肿瘤细胞,或纯化的肿瘤抗原作为疫苗(包括整个蛋白质分子和抗原肽及纯化的DNA分子)来提高免疫系统对肿瘤的识别和排斥.本文从免疫系统对肿瘤细胞的识别、疫苗诱导的体内抗肿瘤免疫的假设机制、疫苗接种所诱导的抗肿瘤反应以及临床结果几个方面,对当前肿瘤疫苗的研究现状作一简要综述,并对肿瘤疫苗研究中尚待解决的问题作了简单的归纳.     

Oncocytic non-functioning endocrine tumor of the pancreas

Herein is presented the case of a malignant non-functioning endocrine tumor of the pancreas with oncocytic features, and a discussion on the high incidence of malignancy in oncocytic endocrine pancreatic tumors. The patient was a 65-year-old woman who showed no paraneoplastic symptoms produced by functioning pancreatic endocrine tumors. The primary tumor was located in the body and tail of the pancreas, and had metastasized to the liver. Tumor cells were arranged in a ribbon-like or trabecular pattern and had an abundant eosinophilic cytoplasm containing numerous mitochondria and neurosecretory granules. The cytoplasm of the tumor cells was intensely stained with an antimitochondrial antigen antibody. Most tumor cells stained positively with Grimelius stain and for chromogranin A. Some tumor cells also stained for synaptophysin. However, the tumor cells negatively stained for hormones such as insulin, glucagon, somatostatin, gastrin, vasoactive intestinal peptide and pancreatic polypeptide, for serotonin, and for pancreatic enzymes such as amylase and trypsin. Analysis of 18 oncocytic pancreatic endocrine tumors, consisting of those reported previously and that in the present case, suggests that the high incidence of malignancy in oncocytic endocrine tumors is associated with the high incidence of non-functioning endocrine tumors among them, most of which are malignant.     

No evidence of endometriosis within serous and mucinous tumors of the ovary

Ovarian endometriosis can transform into malignant tumors. The author retrospectively examined HE slides of 112 serous tumors and 75 mucinous tumors for the existence of ovarian endometriosis. When endometriosis is present within the tumors, the term "endometriosis-derived tumor" was applied. When endometriosis is recognized adjacent to the tumor, the term "endometriosis-associated tumor" was used. Of the 112 serous tumors (46 benign, 18 borderline, and 50 malignant), 4 (3.5%) (2 benign and 2 malignant) were endometriosis-associated tumors. None was endometriosis-derived tumor. Of the 75 mucinous tumors (30 benign, 26 borderline, and 19 malignant), 4 (5%) (1 borderline and 3 benign) were endometriosis-associated tumors. No tumors showed endometriosis-derived tumors. The data suggest that endometriosis does not transform into serous and mucous tumors. The author felt the limitation of retrospective survey, because the limited numbers of slides (5 to 15) were obtained from each tumor. The author also felt that endometriosis can be difficult to discern because of degenerative changes and other similar lesions such as fallopian tube, fimbria, inclusion cysts, rete ovarii, paraovarian cyst, and Müllerian ducts remnants. Prospective study using whole ovarian examination is required.     

艾氏腹水瘤全细胞瘤苗诱导的特异性杀伤活性

目的研究艾氏腹水瘤全细胞瘤苗诱导的特异性杀伤活性。方法用40g/L的多聚甲醛处理的艾氏腹水瘤细胞作为全细胞瘤苗免疫Balb/c小鼠,建立瘤苗小鼠模型。用HE染色法对亲本肿瘤细胞皮下再次攻击形成的肿瘤结节进行病理学观察;用51Cr释放法测定瘤苗免疫组、荷瘤组、正常组小鼠脾细胞,对亲本艾氏腹水瘤细胞和Sp2/0细胞的杀伤活性。结果HE染色显示,经瘤苗免疫后亲本肿瘤细胞皮下再次攻击形成的肿瘤结节中,瘤细胞几乎完全坏死,同时在坏死部位有大量炎细胞浸润、纤维母细胞和小血管增生;而对照组则无以上现象。效靶比为200∶1时,免疫小鼠脾细胞体外杀伤亲本艾氏腹水瘤细胞的杀伤率(％)为(42.3±3.2)％,显著高于荷瘤组的(12.1±2.3)％、正常组的(6.1±1.1)％和对Sp2/0细胞的杀伤率(8.8±0.4)％(P均∨0.05)。结论艾氏腹水瘤全细胞瘤苗可诱导机体产生特异性杀伤活性。     

外泌体与肿瘤的关系及其应用

细胞总是在不断的分泌各种不同类型的微泡到细胞外液,包括一些小分子和大分子,其中之一就是外泌体.最近研究表明其在细胞间通讯以及肿瘤中具有重要作用,因此得到了广泛的关注.在肿瘤形成过程中,外泌体能够利用自身的结构、组成优势调节免疫系统功能,形成利于肿瘤形成的微环境,诱发肿瘤恶性行为,外泌体研究也为肿瘤诊断和治疗提供了新方向.     

Secondary tumors of the pancreas: Clinicopathological study of 103 autopsy cases of Japanese patients

To investigate the clinicopathological features of patients with secondary tumors of the pancreas, we reviewed autopsy records and pathological features of 103 cases with pancreatic secondary tumors from 690 cases of malignant tumors (excluding cases of primary pancreatic cancer) over a 10-year period. There were 67 men and 36 women in the study, ranging in age from 2 to 94 years (mean: 61 years). The incidence of pancreatic secondary tumors was 15% in the autopsy cases of malignant tumors, and the majority of the secondary tumors were carcinomas. The stomach was the most common primary tumor site (20%), followed by the lung (18%) and extrahepatic bile duct (13%). Because the total number of each primary carcinoma differed, we paid specific attention to the incidence of pancreatic metastasis in each primary carcinoma. We found that carcinoma of the papilla of Vater showed the highest rate of incidence (75%) of pancreatic metastasis in each type of primary carcinoma. Approximately half of the metastatic lesions were solitary, but the metastatic lesions in the pancreas could not be identified macroscopically in 34 cases (33%). Histologically, the most common carcinoma was adenocarcinoma, followed by large cell carcinoma, small cell carcinoma and neuroendocrine carcinoma. The most common non-epithelial tumor was leukemia, followed by malignant lymphoma. Undifferentiated carcinoma and neuroendocrine carcinoma were often found in cases of extrahepatic bile duct or urinary bladder carcinoma with pancreatic metastasis. As for the microscopic infiltration patterns of tumor cells, 73% of cases showed an interlobular and intralobular infiltration. Fat necrosis was most frequently seen as an associated pathological finding (19%). Our study indicates that secondary tumors of the pancreas can be found in approximately one out of six to seven autopsy cases of malignant tumors, and in Japan, the most common of these is adenocarcinoma of the stomach.     

Granular cell tumor of the intrapancreatic common bile duct: one case report and review of the literature

A granular cell tumor (GCT) in a 39-year-old white man is reported. It was localized in the intrapancreatic part of the common bile duct and caused obstruction of the bile downflow. The patient underwent radical surgical procedures because a malignant tumor was clinically suspected. Macroscopically, the tumor appeared as a duct stricture caused by diffuse infiltration of neoplastic cells in the walls. In the cytoplasm smaller and larger PAS-positive granules were present and constantly reactive to S-100 and NSE antibodies. Ultrastructurally, cytoplasmic granules appeared as membrane-bound vacuoles of variable size and shape containing debris, disrupted mitochondria, and myelin figures. No basal lamina around cell cytoplasm was observed. GCTs are relatively uncommon soft tissue tumors usually presenting in the skin and subcutaneous tissues or tongue. The prognosis in any location is quite good, but very rare malignant GCTs (1-2%) are documented. Complete excision reduces the risk of recurrence. Accurate operative diagnosis seems to be critical when the tumors are located in the intrapancreatic common bile duct as in this reported case. Gastro-pancreatico-duodenectomy is too radical a procedure for such a benign lesion and additional assessments and investigations are recommanded before such an extensive radical surgery.     

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61‐year‐old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis. Diagn. Cytopathol. 2011;39:278–282. © 2010 Wiley‐Liss, Inc.     

Clinicopathological analysis on cancers of autopsy cases in a geriatric hospital

It is generally accepted that cancers in the eiderly are of low grade mallgnancy. In order to clarify this point, autopsy cases from a medical center for the elderly between 1982 and 1994 were pathologlcally analyzed. Three hundred and fifty (160 males, 190 females) out of a total of 871 (361 males, 510 females) autopsy cases were examined. The Incidence of cancer In varlous age groups were found to be as follows: <69 years, 24/67 (36%); 70–74 years, 401102 (39%); 75–79 years, 54/136 (39%); 80–84 years, 79/180 (44%); 85–89 years, 66/172 (38%); 90–94 years, 59/137 (43%); 95–99 years, 17/56 (30%); and >100 years, 12/21 (57%). The incidences did not significantly differ among the groups, that is, there was no age-dependency in the Incidence of cancer. Furthermore, the incidences of multiple cancers (two or more different malignancies In one patient) also did not differ. However, deaths due to the cancers showed a tendency to decrease with age. The survival periods of clinical cancer cases without a surgical operation history (time period between the date of diagnosis and death), were age-related for female cases. However, the rate of distant metastasis was not age-related. The incidence of latent cancers in individuals over 85 years of age was 79/174 (45.4%) and significantly higher than the value of 69/234 (29.5%) for those under 85. The number of malignant tumors in various organs for the different age groups was also counted and the total numbers of clinical cancers and latent cancers in each organ were, 50 and 23 in the lung, 46 and 20 in the stomach, 41 and 31 in the colon, 0 and 39 in the prostate, and 14 and 0 in the mammary glands, respectively. All prostate cancers were latent cancers, and all mammary cancers were clinical cancers. These findings provide strong evidence that cancers In individuals of advanced age have less mailgnency potential.     

靶向肿瘤干细胞的免疫疗法

由于肿瘤干细胞(TSCs)与肿瘤的发生﹑发展﹑转移﹑复发和耐药等有着密切关系,是肿瘤的根源细胞,意味着治愈肿瘤的关键途径可能在于根除TSCs。因传统的手术﹑化疗和放疗等对肿瘤治疗的方法无法杀死TSCs,容易导致肿瘤转移和复发,而靶向TSCs的免疫疗法已确定能杀伤TSCs,如靶向TSCs的表面抗原﹑T细胞靶向TSCs的应用和分化疗法等。     

Review: Putative mutagens and carcinogens in foods III. Butylated hydroxytoluene (BHT)

Although the average American's daily consumption of BHT can be measured in milligrams, there are numerous reports that BHT causes organ damage in laboratory animals. Only a few genotoxic effects of BHT have been reported, however, including mutagenicity in the abnormal sperm assay and ambiguous results regarding its teratogenicity. More dramatic are the modulatory effects of BHT on the actions of established mutagens and carcinogens. BHT can either enhance or inhibit mutagenic potency, depending on the substance tested. For example, in the Ames test, BHT is antimutagenic towards benzo(a)pyrene, but increases the number of Salmonella revenants induced by aflatoxin B₁. BHT is one of the few compounds to have both tumor prophylactic and tumor promoting capacities. It is the temporal sequence in which BHT and carcinogens are administered to test animals which determines how BHT affects the response to these carcinogens. In common with other antioxidants, BHT inhibits the ability of carcinogens to induce tumors in various rodent organs when the animal is given BHT prior to carcinogen treatment. Unlike other antioxidants, however, the number of tumors increase when BHT is administered after carcinogen exposure. The comutagenic and cocarcinogenic properties of BHT have been demonstrated in tests ranging from the Ames test to cell transformation procedures to in vivo assays. These effects are probably mediated by metabolites of BHT, rather than by BHT itself.     

过氧化物酶体增殖物激活受体-γ与肿瘤

PPAR-γ是一种细胞核转录因子,与糖代谢调节、脂肪细胞分化相关。其配体除了具有改善胰岛素抵抗和血脂、免疫调节和抗炎作用外,还具有抗肿瘤细胞增殖和促细胞分化作用,对肿瘤细胞的转移、侵袭等生物学行为也有影响。其机制可能是诱导细胞周期停滞和凋亡,促进细胞分化,通过抑制NF-κB活性和阻断EGFR信号通路起抑制肿瘤细胞生长的作用     

Tumor-derived microparticles in tumor immunology and immunotherapy

Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus, remodeling tumor microenvironments and resetting antitumor immune responses, thus, conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy.     

Pulmonary tumor thrombotic microangiopathy

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by widespread fibrocellular intimal proliferation of the small pulmonary arteries and arterioles in patients with metastatic Carcinoma. Microscopic pulmonary tumor emboll have frequently occurred in patients with malignant tumors; however, few cases of PTTM have been reported. A rare case of a patient with gastric adenocarcinoma who presented with acute dyspnea and lethal respiratory failure is described. Histologically, diffuse fibromuscular intimal thickening cauring luminal stenosis and obstruction but containing rather few cancer cells was observed in the small pulmonary arteries and arterioles. These findings were consistent with PTTM. Atthough PTTM is a rare phenomenon, PTTM should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with carcinoma.     

肿瘤治疗电场的微观机制及临床应用进展

肿瘤治疗电场（TTFields）使用非侵入式一次性传感器阵列提供低强度、中频、交变电场干扰细胞有丝分裂导致发生应激、凋亡及增值抑制,达到局部治疗肿瘤的目的。TTFields通过干扰微管蛋白二聚体在微管上的正常组装和拆卸来破坏有丝分裂期肿瘤细胞的染色体分离;通过对Septin蛋白复合物、非肌肉肌球蛋白II和纤维型肌动蛋白等具有高偶极矩的蛋白质施加旋转、扭转应力等物理力破坏卵裂沟的形成和收缩;通过在有丝分裂细胞内形成的不均匀电场诱发介电泳现象破坏细胞质的分离。TTFields对于不同的细胞具有不同的敏感参数,对静止期细胞则没有作用。TTFields与化疗联合应用具有相加或协同作用,可以提高疗效。TTFields具有创伤小、副作用较小的优势,安全性和有效性在胶质母细胞瘤的III期临床试验中得到验证,在其它多种癌症也开展了临床研究。     

Pleomorphic hyalinizing angiectatic tumor of soft parts: a case report and literature review

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, recently recognized neoplasm occurring predominantly in the subcutaneous tissue of the lower limbs of adults. We report a case of PHAT in an 83-year-old woman who presented with a 5.0 x 5.0 x 2.0 cm mass in the soft part of her left thigh. Histologically, the tumor was well circumscribed by a thin fibrous capsule and predominantly composed of fusiform cells with eosinophilic cytoplasm and round-to-oval or pleomorphic nuclei. The tumor cells resembled those of malignant fibrous histiocytoma, but differed from them by less prominent mitotic figures. Immunohistochemically, the tumor cells were diffusely and strongly positive for CD34; partially positive for vimentin and CD99 (MIC-2); and negative for epithelial and non-epithelial markers. Ultrastructurally, the tumor cells had pleomorphic cytoplasm and nucleus. Intermediate-sized cytoplasmic filaments were observed in a few tumor cells, but neurosecretory-type granule-like intracytoplasmic organelles were not seen. These findings suggest that this tumor is derived from stromal fibroblast, such as solitary fibrous tumors or giant cell angiofibroma.