Protein-bound polysaccharide-K (PSK) induces apoptosis and inhibits proliferation of promyelomonocytic leukemia HL-60 cells

Protein-bound polysaccharide-K (PSK) is extracted from Coriolus versicolor (CM101), and is clinically used in combination therapy for gastrointestinal cancer and small cell lung carcinoma. PSK is a biological response modifier (BRM), and its mechanism of action is partly mediated, by modulating host immune systems, such as the activation of immune effector cells and the neutralization of transforming growth factor-beta (TGFβ) activity. Direct inhibition of tumor cell proliferation has been reported as another mechanism, but how PSK induces such an effect remains to be elucidated. Here, the anti-proliferative activity of PSK was examined using seven different human malignant cell lines (WiDr, HT29, SW480, KATOIII, AGS, HL60 and U937), and PSK was found to inhibit the proliferation of HL-60 cells most profoundly. Therefore, HL-60 cells were used to clarify the mechanism of anti-proliferative activity. Caspase-3 activation followed by apoptosis are involved at least in part in the PSK-induced anti-proliferative activity against HL-60 cells.     

Evaluation of immunotherapy with PSK in esophageal cancer

The cooperative study group of PSK for resected squamous cell carcinoma of esophagus was formed among 18 institutes in Japan to evaluate the efficacy of PSK. From February 1983 to November 1985, a total of 187 patients were entered into this study. Some 140 of them were judged to have received complete therapy. PSK was used as an immunopotentiator in combination with radiotherapy (I-A, I-B) and radiochemotherapy (II-C, II-D). The selection of radiotherapy or radiochemotherapy was entrusted to each institute. The two-year survival rates of I-A, I-B, II-C and II-D were 59.7%, 54.5%, 40.1% and 54.1%, respectively. From these observations, PSK was considered beneficial for esophageal cancer in combination with radiochemotherapy.     

Usefulness of polysaccharide K (PSK) as postoperative adjuvant immunotherapy in patients with stage IV gastric cancer

Background. We investigated retrospectively the usefulness of polysaccharide K (PSK) administration for prolonging survival after noncurative resection in patients with stage IV gastric cancer who underwent surgery at our department. Methods. 357 patients with gastric cancer evaluated as stage IV according to thegeneral rules for gastric cancer study, 11th edn (1985) of the Japanese Research Society for Gastric Cancer, who were expected to succumb to surgical death or postoperative death within 2 months were studied. The patients were divided into two groups: total PSK dosage greater than or less than 180g. Survival rates were calculated for each group. Results. In these stage-IV gastric cancer patients, the 5-year and 10-year survival rates in the PSK group were both 13.9%. In the non-PSK group, the rates were 8.7% and 7.0%, respectively. The survival rates were significantly higher in the PSK group (p = 0.0001). The survival rate was also calculated with respect to the staging factors. Patients in the PSK group who had H0, P0, se or milder and n3 or n4 showed a significantly higher survival rate than those with these staging factors in the non-PSK group (p = 0.010). Conclusion. PSK administration prolonged survival in stage-IV gastric cancer patients, the effect being marked in patients with severe lymph node metastasis. We suggest that be administered as adjuvant therapy in stage-IV gastric cancer patients with severe lymph node metastasis (n3, n4).     

Breast cancer resistance mechanisms: challenges to immunotherapy

Breast Cancer Research and Treatment - The clinical implementation of immunotherapy has profoundly transformed cancer treatment. Targeting the immune system to mount anti-tumor responses can elicit...     

Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies

Immune checkpoint blockade(ICB) therapy has recently shown promise in treating several malignancies. However, only a limited number of patients respond to this treatment, partially because of the “immune cold” condition of the tumor immune microenvironment. Pyroptosis is a type of gasdermin-mediated programmed cell death that often leads to inflammation and immune responses. Many studies on the mechanism and function of pyroptosis have led to increasing recognition of the role of pyroptosis in m...     

Krestin (PSK)

A polysaccharide preparation isolated from Coriolus versicolor (Fr.) Quél. of Basidiomycetes (PSK) predominantly consists of glucan and approximately 25% tightly bound protein. PSK was effective against various allogeneic and syngeneic animal tumors and has been given orally to cancer patients. Various suppressed or enhanced immune responses of tumor-bearing animals were restored to normal levels by the administration of PSK in the tumor models tested. The killer T cell activity was augmented in tumor-bearing mice by intraperitoneal or oral administration of PSK, and there was correlation between the PSK associated antitumor effect and the killer T cell activity. It was found that PSK competed with immunosuppressive substances isolated from tumor-bearing mice and that the intestinal immune system appeared to be modulated by oral administration of PSK. After oral administration of 14C- or 35S-labeled PSK to normal rats, it was found that small or large molecular substances appeared in the serum depending on the time elapsed after administration, an indication that large molecular size products were from the digestive tract.     

Apoptosis: mechanisms and implications for cancer therapeutics

Apoptosis, or programmed cell death, is essential for many physiological and pathological processes. Apoptosis results from an orderly activation of several cysteine proteases called caspases, which can be classically triggered by two upstream pathways: the intrinsic and extrinsic pathways. Deregulation of apoptosis is essential for tumor growth and a hallmark of cancer cells. In the recent years, many key elements of the apoptotic process have been identified and have become strategic targets for anticancer therapy. The novel approaches that target the apoptotic pathway may have either a direct proapoptotic effect or alternatively may sensitize cancer cells to other cytotoxics. This review describes the major elements of the apoptotic process, with a special focus of the tight interactions between the extrinsic and intrinsic pathways, and summarizes some of the most promising implications for cancer therapeutics.     

Immunomodulatory effects of low dose cis-Diaminedichloroplatinum (cisplatin) combined with UFT and PSK in patients with advanced colorectal cancer

It is well known that cell-mediated immunity is suppressed in patients with neoplastic diseases. We have reported that soluble receptors for interleukin-2 (sIL-2R) and tumor necrosis factor (sTNF-R1) are elevated in the serum of patients with advanced colorectal cancer. The presence of these soluble receptors and immunosuppressive cytokines, including interleukin-10 (IL-10), might be important in the mechanisms of immunosuppression. cis-Diaminedichloroplatinum (cisplatin) has been reported to immunomodulate, especially when used in low dose in combination with 5-Fluorouracil (5-FU). In this study, cisplatin and UFT, a form of uracil and tegafur which is a prodrug of 5-FU, were administered with immunomodulator Polysaccharide K (PSK) to ten patients with colorectal cancer, who showed distant metastasis in the liver or lung, and the serum levels of sIL-2R and sTNF-R1 and the production of gamma-interferon (gamma-INF) and interleukin-10 by peripheral blood mononuclear cells were measured. The serum concentrations of sIL-2R and the production of IL-10 were reduced (p < 0.05) after 2 months of treatment. Thus, this combination appeared to have immunomodulative potential in patients with advanced colorectal cancer.     

肿瘤免疫治疗和化疗的协同效应及其作用机制

近年来肿瘤治疗领域受到关注的热点之一是免疫治疗与化疗的联合应用,大量基础与临床的研究结果表明,恰当的免疫化疗（chemoimmunotherapy） 能够取得较单一疗法更优的抗肿瘤效果,超越了以往认为化疗对免疫系统具有抑制作用、免疫治疗与化疗难以一起应用的传统观念。免疫化疗具有协同抗肿瘤效果的机制是多方面的,化疗可通过增强肿瘤细胞免疫原性、去除免疫抑制以及调节免疫应答反应等方式增强免疫治疗效果;另外,免疫治疗能够逆转肿瘤细胞的化疗耐药性,从而提高肿瘤细胞对化疗药物的敏感性并降低化疗的毒性作用等。目前,肿瘤免疫治疗与化疗协同作用的机制尚未完全清楚,相信通过其相关机制的不断阐明,将进一步提高免疫化疗的抗肿瘤效果并推动其临床应用。     

Immune response drives outcomes in prostate cancer: implications for immunotherapy

The heterogeneity of the immune microenvironment leads to different responses in immune checkpoint blockade therapy. We aimed to propose a robust molecular classification system to investigate the relevance of the immune microenvironment subtype and prognosis of prostate cancer patients, as well as the therapeutic response to immune checkpoint blockade therapy. A total of 1,557 prostate cancer patients were enrolled, including 69 real‐world samples from our institute (titled the AHMU‐PC cohort). The non‐negative matrix factorization algorithm was employed to virtually microdissect patients. The immune enrichment was characterized by a high enrichment of T cell‐, B cell‐, NK cell‐, and macrophage‐associated signatures, by which patients were subclassified into nonimmune and immune classes. Subsequently, the immune class was dichotomized into immune‐activated and immune‐suppressed subtypes based on the stromal signature, represented by the activation of WNT/TGF‐β, TGF‐β1, and C‐ECM signatures. Approximately 14.9% to 24.3% of patients belonged to the immune‐activated subtype, which was associated with favorable recurrence‐free survival outcomes. In addition, patients in the immune‐activated subtype were predicted to benefit more from anti‐PD‐1/PD‐L1 therapy. In conclusion, our study identifies a novel immune molecular classifier that is closely related to clinical prognosis and provides novel insights into immunotherapeutic strategies for prostate cancer patients.     

Anticancer therapy and lung injury: molecular mechanisms

Introduction: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities.

Areas covered: As we move toward the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury.

Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their antitumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.     

化疗对肿瘤免疫治疗的增益作用

传统观念认为化疗以后机体免疫功能低下,化疗后不应随即实施肿瘤免疫治疗。由于缺乏客观、精确的指标从体内实验去评判化疗与免疫治疗的关系,这方面的研究工作一直寥寥无几。近年来,随着肿瘤学和免疫学研究的深入发展,上述课题的探索取得了一些欣喜的结果,即化疗药物诱导的凋亡肿瘤细胞能够有效诱发免疫应答,并通过增加肿瘤抗原交叉提呈量、减少Treg细胞的数量并抑制其功能、促进肿瘤细胞减灭、使APCs对CD40信号的敏感性增强、影响机体细胞因子网络、影响效应T细胞移行及肿瘤免疫记忆产生等途径,对随后的免疫治疗起到增益作用。该增益作用已被日益增多的动物实验和临床报告所证实。     

化疗对肿瘤免疫治疗的增益作用

由全军免疫学专业委员会主办、第二军医大学免疫学研究所承办、河南大学医学院协办的第六届全军免疫学学术交流会将于2007年4月20—23日在河南开封召开。会议将就上一届会议（上海，1999年12月）以来全军基础与临床免疫学研究的进展及国内外免疫学研究现状和发展趋势作充分交流和讨论。会议将特邀国内知名的专家学者作专题报告。[第一段]     

Trastuzumab (Herceptin) and breast cancer: mechanisms of resistance

The detection of overexpression of human epidermal growth factor receptor 2 (HER2) in some breast cancer tumors has led to the development of a targeted treatment that is tumor selective, effective at extending life expectancy in the patients with advanced or early breast cancers. Trastuzumab (Herceptin), a humanized monoclonal antibody to HER2 is indicated for patients whose tumor demonstrates an amplified copy number for the HER2 oncogene and/or overexpresses the HER2 oncoprotein. Despite a high level of efficacy in combination with chemotherapy, trastuzumab as single agent has limited effectiveness (up to 30% response rates) and patients who respond to trastuzumab will relapse despite continued treatment. The mechanism of trastuzumab action is not fully understood but has been related to cell cycle inhibition. As to mechanisms of resistance, little is known but many preclinical data raised different hypothesis. Thus, the co-expression of growth factor receptors (EGFR family, IGF-1 R), and the activation of PI3K-Akt pathway, mainly by loss of PTEN function may be responsible for the resistance phenotype. It would be interesting to identify the mechanisms of trastuzumab resistance in breast tumors in order to reverse or prevent it. The characterization of these mechanisms would also provide novel strategies for alternative treatments.     

Experimental study on immunochemotherapy (PSK, CQ) in rat bladder cancer (BC-47)

Cancer of the urinary bladder is a tumor with the highest frequency among urogenital cancers, and more-over, its recurrence rate is high. It is considered important and urgently necessary to conduct studies into the prevention of recurrence of this cancer. We have started a Study Group on Postoperative Maintenance Therapy for Bladder Tumor (Tokyo), and conducted group studies on the prevention of recurrence. Fundamental experiments have been performed, and the following results obtained. Antitumor effects of PSK in combination with CQ for bladder carcinoma were studied using male ACI rats. An established bladder carcinoma cell line, BC47 was transplanted into the backs of rats subcutaneously prior to the administration of PSK and CQ. Inhibitory effect on tumor growth and prolongation of survival period were examined. Although single-agent PSK or CQ both had inhibitory effects on transplanted tumors as well as on metastatic tumors in the lung, more remarkable effects were noticed as a result of combination treatment. Prolongation of lifespan using combination therapy was superior to that using single treatment and the rats of decrease in body weight was also lower. These results do not necessarily clarify the antitumor mechanisms, but the immune system, probably non-specifically, may take part in the mechanism judged from the accumulated results obtained from in vivo systems. We think that the combinational effects of these two drugs on general condition are probably originated from inhibition of tumor growth since the inhibition, prolongation of lifespan, change of body weight and so on were closely correlated with each other. However, the direct effect of these drugs may also be counted. The combination therapy of PSK and CQ seemed to be useful against rat bladder carcinoma, BC47. We therefore intend to proceed with group study trials of Postoperative Maintenance Therapy for Bladder Tumor.     

A case of remarkable regression of lung adenocarcinoma with PSK immunotherapy

An asymptomatic 84-year-old man was admitted to our hospital for a further examination of an abnormal shadow in the right lower lung (S9) on chest X-ray film. Sputum and specimens of transbronchial brushing showed cytological characteristics of well differentiated adenocarcinoma. Considering his age, his family did not agree to any surgical operation, irradiation or intensive chemotherapy. Therefore, using PSK: 3.0 g/day, immunotherapy was started on October 26, 1984. However, the abnormal density continued to increase in size and was observed radiographically to infiltrate to the neighboring segment (S6) over the following four months. From March 1985, the tumor regressed gradually and had almost disappeared on chest X-ray films by December 1985. Since then, this remission has been maintained by administration of PSK alone (3.0 g/day).     

Effects of TGF-beta on the immune system: implications for cancer immunotherapy.

Transforming growth factor-beta (TGF-beta) is a potent regulator of numerous processes including hematopoiesis, cell proliferation, differentiation and activation. TGF-beta has pleiotropic and profound effects on the immune system and on hematologic malignancies, ie leukemia. It is the most potent immunosuppressor described to date. Evidence exists that the immunosuppressive potential of TGF-beta is an important promoter of malignant cell growth. This is partly caused by TGF-beta-induced interference with the generation of tumor-specific cytotoxic T lymphocytes, but also by TGF-beta-induced promotion of angiogenesis and tumor stroma formation. Until now, significant clinical responses have not been achieved with the current cancer immunotherapeutic approaches. One of the possible explanations for this failure is immunosuppression induced by tumor-derived TGF-beta. Here, several strategies to counteract the immunosuppressive effects of TGF-beta and the current limitations of these strategies will be discussed. Knowledge of the mechanisms by which TGF-beta interferes with the development of an anti-tumor response and of the strategies to counteract these immunosuppressive activities is crucial to improve the current cancer immunotherapeutic approaches.     

Lymphatic vessels and lymphangiogenesis in female cancer: mechanisms, clinical impact and possible implications for anti-lymphangiogenic therapies (Review)

Lymphatic vessels play a crucial role in a variety of human cancers, since invasion of lymphatic vessels by tumor cells and subsequent development of lymph node metastases significantly influences prognosis of cancer patients and therefore represent an integral part of tumor staging. Recent evidence on the important influence of lymphangiogenetic growth factors on intralymphatic cancer growth and metastasis raises hopes that lymphatic vessels and factors inducing their growth could serve as an additional target for tumor therapy. Nevertheless, in contrast to blood vessel angiogenesis, the mechanisms of new lymphatic vessel formation in human cancers, i.e. lymphangiogenesis, are still relatively unclear. In addition, only little data exist so far on the quantification and impact of this lymphangiogenesis, evident by lymphatic microvessel density (LMVD), on the prognosis of cancer patients. With expectation of possible anti-lymphangiogenic therapies, this review focuses on the mechanisms of lymphangiogenesis in general, and especially on the role of lymphatic vessels in gynecological and breast cancer, which are the so far most detailed investigated malignancies with regard to lymphangiogenesis.     

丹参酮抗肿瘤作用及其机理的研究

丹参酮是从活血化瘀中药丹参中提取的脂溶性有效成分,临床主要用于治疗心血管疾病。近年研究表明,丹参酮对多种肿瘤细胞具有细胞毒作用,并可诱导肿瘤细胞分化和凋亡,抑制肿瘤细胞侵袭和转移;其作用机理可能与抑制癌细胞DNA合成,影响肿瘤细胞增殖、分化和凋亡相关的多种基因表达,抑制癌细胞端粒酶活性,改变肿瘤细胞表面抗原表达等有关。