Can combination of osteopontin and peritumor-infiltrating macrophages be a prognostic marker of early-stage hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is one of the most frequent malignancy worldwide. The increasing incidence of HCC in the worldwide has sparked an emerging interest in prognostic markers of HCC. Osteopontin (OPN) is a secreted phosphoprotein which has been associated with progression and metastasis of HCC. Also, peritumoral macrophage (PTM) have been reported to facilitate tumor progression and metastasis. Recently, one study reported that combination of OPN with PTM may predict the prognosis of HCC after curative resection. The authors successfully identified that combination of these two markers is an independent predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. These findings might support the possibility that combination of OPN and PTM levels can be a prognostic tool. However, further investigations should be conducted before tumor OPN combined with PTMs can be accepted as a valid prognostic marker in clinical practice.     

Inflammation and cancer

There is evidence supporting the hypothesis that inflammation participates in providing conditions that lead to cancer.An unresolved inflammation due to any failure in the precise control of the immune response can continue to perturb the cellular microenvironment, thereby leading to alterations in cancer-related genes and posttranslational modification in crucial cellular proteins involved in the cell cycle,DNA repair and apoptosis.In addition,there are data indicating that inflammatory cells and immunomodulatory mediators present in the tumor microenvironment influence tumor progression and metastasis.Historically,tumor-infiltrating leukocytes have been considered to be manifestations of an intrinsic defence mechanism against developing tumors.However,increasing evidence indicates that leukocyte infiltration can promote tumor phenotypes, such as angiogenesis,growth and invasion.This may be due to inflammatory cells that probably can influence cancer promotion by secreting cytokines,growth factors,chemokines and proteases,which stimulate proliferation and invasiveness of cancer cells.Conse-quently,events and molecules implicated in this cross talk between the tumor microenvironment and inflam- matory process may emerge as attractive targets in anticancer therapeutic interventions with significant clinical impact.     

Combination of Osteopontin with Peritumoral Infiltrating Macrophages is Associated with Poor Prognosis of Early-Stage Hepatocellular Carcinoma after Curative Resection

Background

Crosstalk between a tumor and the microenvironment plays a key role in tumor progression and metastasis. This study was performed to elucidate the prognostic significance of combining tumor-secreted osteopontin (OPN) with microenvironment-associated peritumoral macrophages (PTMs) in hepatocellular carcinoma (HCC), especially for those with early-stage disease.

Methods

Tissue microarray-based immunohistochemistry was used to investigate OPN and PTMs expression in two independent cohorts consisting of 374 patients with HCC who underwent radical resection. The prognostic value for the two factors alone or in combination was investigated in these patients.

Results

OPN combined with PTMs was an independent prognostic factor for both overall survival (OS; p < 0.0001) and time to recurrence (TTR; p = 0.003) from the learning cohort (n = 96). Their combined value for prognosis was validated in early-stage HCCs using another independent cohort (n = 278; OS, p < 0.001; TTR, p = 0.001). This combination remained significant in HCCs with low α-fetoprotein levels in both cohorts, and was predictive for early recurrence/death risk (<2 years) compared with a single marker. Only OPN+HCCs had a significant correlation of PTMs levels with OS (p = 0.01) or TTR (p = 0.011).

Conclusions

Tumor OPN combined with PTMs is a promising predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. The interplay of OPN and PTMs represents a new insight into tumor progression and therapeutic targets for HCC.     

Prostate tumor progression and prognosis. interplay of tumor and host factors

The prognosis for prostate cancer is largely dependent on the probability of metastatic dissemination. Prognostic markers currently in use are very poor predictors of metastatic potential, and as of yet none of the battery of new molecular markers has proven greatly superior. This may be due in part to their inability to assess the degree of interaction of subpopulations of prostate cancer cells with each other and with their microenvironment. A growing body of evidence indicates that these types of interactions are a major factor in the eventual genesis of cancer cells capable of metastasis. Recent research has demonstrated that specialized components of prostate tumors may play a critical supporting role for the overall growth of the larger tumor. The multifocal nature and apparent polyclonal origins of prostate tumors suggest that carcinogenesis and tumor progression are promoted by global influences or “field effects.” It appears that these effects extend beyond the proliferating epithelial component to the tissue stroma. Prostate cancer cells and stromal cells seem to act in concert to modify the microenvironment, leading to metastasis. An understanding of this synergy may provide a new class of prognostic markers which more accurately measure the complex set of interactions that determine tumor behavior.     

肝细胞癌免疫微环境研究进展及未来方向

肝细胞癌（HCC）是我国一种常见的恶性肿瘤,肿瘤微环境在疾病的发生、发展中起着至关重要的作用。除肿瘤细胞外,HCC的免疫微环境由基质细胞（包括淋巴细胞、中性粒细胞、巨噬细胞、成纤维细胞等）、结构成分（如细胞外基质等）和细胞间通讯相关分子（趋化因子、细胞因子、生长因子、外泌体等）组成,这些细胞影响着肿瘤免疫逃逸、对免疫治疗的反应和病人的预后。近年来,针对HCC的免疫治疗方法展现了一定的潜力。但是治疗反应率仍不令人满意。更好地了解HCC免疫微环境中各成分之间的串扰,并从中挑选潜在的治疗靶点,有助于预测免疫治疗反应、判断免疫治疗疗效、发现预后标记物及选择个体化治疗方案。     

Molecular insights into prostate cancer progression: the missing link of tumor microenvironment

PURPOSE: Tumor cell genotype and phenotype have been considered the only determinants supporting cancer growth and metastasis. This review focuses on the published literature that suggests that tumor-microenvironment interaction has a decisive role in controlling local cancer growth, invasion and distant metastasis. As this review shows, genetic alterations in prostate cancer cells alone are not enough to confer metastatic status without a supporting tumor microenvironment. Effective therapeutic targeting requires a deeper understanding of the interplay between tumor and stroma. Approaches co-targeting tumor and stroma already show promise over the conventional targeting of tumor cells alone in preventing prostate cancer progression and eradicating preexisting or newly developed prostate cancers in bone and visceral organs. MATERIALS AND METHODS: A literature survey using the MEDLINE database was performed in basic and clinical publications relevant to tumor-host microenvironment interaction. Information pertinent to the biology and therapy of prostate cancer local growth and distant metastases was specifically emphasized. RESULTS: Tumor associated stroma actively fuel the progression of prostate cancer from localized growth to the invasion of surrounding tissues, and the development of distant bone and visceral organ metastasis. In concert with this progression tumor cells recovered from metastatic sites could represent a subpopulation of preexisting tumor cells or could be a newly acquired variant subsequent to tumor-stromal interaction. Experimental data from our laboratory and others suggest that permanent genetic and phenotypic changes occur in prostate cancer cells after 3-dimensional co-culture in vitro or when co-inoculated and grown with inductive stromal cells in vivo. These results support the idea that newly acquired variants are the dominant mechanism of prostate cancer progression. Intercellular communication between prostate cancer cells and organ specific stroma, including prostate and marrow stroma, could involve diffusible soluble and solid matrix molecules as mediators, leading to the development of metastasis. This presents a new opportunity for therapeutic targeting for the treatment of benign and malignant growth of the prostate glands. This review summarizes specific research implicating tumor-microenvironment interaction as the molecular basis of cancer progression, providing a rationale for targeting tumor and the tumor associated microenvironment in the management of androgen independent and bone metastatic prostate cancer progression in patients. CONCLUSIONS: Cancer is not a single cell disease. Aberrant cancer cells and their interactive microenvironment are needed for prostate cancer to progress to androgen independence and distant metastasis. It is highly plausible that newly evolved prostate cancer cell clones dominate cancer metastasis after cell-cell and cell-matrix interaction with the host microenvironment, rather than the selection or expansion of a preexisting prostate cancer cell clone(s). Based on this premise potential molecular targets in the microenvironment are especially emphasized. Further elucidation of the molecular mechanisms underlying tumor-stromal interaction may yield improved medical treatments for prostate cancer growth and metastasis.     

Exosomes在肿瘤微环境中的作用

肿瘤微环境是指肿瘤细胞在生长过程中,由肿瘤细胞及细胞外间质相互作用后形成的肿瘤细胞生长的特殊环境.肿瘤微环境作为保护和支持肿瘤发生、发展及转移复发的必要机构功能单元的理论已为越来越多的学者所接受.而最新的研究证据表明,exosomes在肿瘤微环境中,参与了细胞与细胞间的沟通,对肿瘤的进展可能起到了举足轻重的作用.本文总结近年来的文献,就exosomes的性质、生物学作用以及作为肿瘤微环境的重要组成部分在肿瘤进展中的潜在作用作一综述.     

胰腺星状细胞在胰腺癌治疗中的应用价值研究进展

胰腺癌因其复杂的肿瘤微环境（TME）,具有恶性程度高、进展快、转移早、化疗耐药及无特殊靶向药物等特点。胰腺星状细胞（PSCs）是胰腺的常驻脂质储存细胞,是TME的重要组成部分,靶向TME中的肿瘤-基质串扰已成为一种有前途的抗胰腺癌进展和转移的治疗策略。因此,笔者就PSCs在胰腺癌TME中的相互作用及靶向活化PSCs的潜在治疗应用进行综述,以期为胰腺癌的治疗提供新靶点和新思路。     

血小板在肝细胞癌发生和转移中的研究进展

肝细胞癌(HCC)是临床上最常见的原发性肝癌,其发生、发展通常与慢性炎症和肝损害有关。血小板不仅是肝损伤后再生的基础,而且在促进HCC发生和转移中所起的作用也得到较多关注。血小板既能在HCC肿瘤微环境中直接诱导肿瘤细胞生长和帮助肿瘤细胞躲避免疫杀伤,又能通过分泌的特异性生长因子和血管生成因子诱导肿瘤滋养血管生成促进HCC进展。此外,血小板相关衍生物也对HCC肿瘤细胞的增殖和转移存在重要影响。详细了解血小板在HCC中的作用,对于优化HCC肿瘤治疗方案和探索新的治疗策略很有必要。本综述详细报道血小板在HCC发生和转移中作用的相关机制及最新研究进展。     

Cell Motility and Cytoskeletal Regulation in Invasion and Metastasis

Cell motility and chemotaxis can make important contributions to the metastatic cascade. Cell migration pathways in general play significant roles in a variety of physiological processes that can be “hijacked” by cancer cells. Both growth factors and chemokines provide important chemotactic signals in development and metastasis. Receptor activation, following binding of a growth factor or a chemokine, leads to dynamic morphological changes in the actin cytoskeleton network via a variety of distinct and interconnected pathways, resulting in translocation of the cell up a chemoattractant gradient. Such gradients may be produced by stromal cells in the local microenvironment, including macrophages and fibroblasts. A better understanding of the mechanisms of cell motility and cytoskeletal regulation may provide novel therapeutic strategies that would block metastatic progression, reducing dissemination of tumor cells and increasing patient survival.     

High Expression of Proline-Rich Tyrosine Kinase2 is Associated with Poor Survival of Hepatocellular Carcinoma via Regulating Phosphatidylinositol 3-Kinase/AKT Pathway

Background

The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism.

Methods

Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation.

Results

Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K–AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells.

Conclusions

High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.

     

Metastasis Suppressors and Their Roles in Breast Carcinoma

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Clinically and experimentally, primary tumor development and metastasis are distinct processes—locally growing tumors can progress without the development of metastases. The discovery of endogenous molecules that exclusively inhibit metastasis suggests that metastasis is an amenable therapeutic target. By definition, metastasis suppressors inhibit metastasis without inhibiting tumorigenicity and are thus distinct from tumor suppressors. As the biology underlying functional mechanisms of metastasis suppressors becomes clearer, it is evident that metastasis suppressors could be harnessed as direct drug targets, prognostic markers, and to understand the fundamental biology of the metastatic process. Metastasis suppressors vary widely in their cellular localization: they are found in every cellular compartment and some are secreted. In general, metastasis suppressors appear to regulate selectively how cells respond to exogenous signals, by affecting signaling cascades which regulate downstream gene expression. This review briefly summarizes current functional and biochemical data on metastasis suppressors implicated in breast cancer. We also present a schematic integrating known mechanisms for these metastasis suppressors highlighting potential targets for therapeutic intervention.     

Competing endogenous RNA network analysis reveals pivotal ceRNAs in bladder urothelial carcinoma

BackgroundBladder urothelial cancer (BUC) has become one of the most frequently occurring malignant tumors worldwide and it is of great importance to explore the molecular pathogenesis of bladder cancer. Emerging evidence has demonstrated that dysregulation of noncoding RNAs is critically involved in the tumorigenesis and progression of BUC. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression and therefore form a competing endogenous RNA (ceRNA) network. ceRNA networks have been proven to play vital roles during tumorigenesis and progression. Elements involved in the ceRNA network have also been identified as potential therapeutic targets and prognostic biomarkers in various tumors. Understanding the regulatory mechanisms and functional roles of the ceRNA system will help understand tumorigenesis, progression mechanisms of BUC and develop therapeutics against cancer.MethodsIn this study, we utilized the TCGA database and analyzed the multilevel expression profile of BUC. ceRNA regulatory networks were constructed by integrating tumor progression and prognosis information. RNA immunoprecipitation (RIP) and qRT-PCR were applied to verify the identified ceRNA networks. KEGG enrichment analysis was implemented to infer the biological functions of the regulatory system.ResultsWe identified a lncRNA–miRNA–mRNA regulatory ceRNA network containing two lncRNAs, one miRNA and 14 mRNAs. The ceRNA network we identified showed significant roles in BUC tumorigenesis, progression, and metastases.ConclusionsThe proposed ceRNA network may help explain the regulatory mechanism by which lncRNAs function as ceRNAs and improve our understanding of the pathogenesis of BUC. Moreover, the candidate elements involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for BUC.     

调节性T细胞与原发性肝癌的免疫治疗

原发性肝癌的免疫治疗近年来发展迅速,在基础和临床前期研究中取得了令人鼓舞的治疗成果.但和其它恶性肿瘤类似,肝癌存在着严重的肿瘤免疫微环境抑制,大大影响了肝癌免疫治疗的效果.调节性T细胞(Treg)是一类免疫负性调控细胞,在维持人体自身免疫稳定和抗肿瘤免疫过程中起着重要作用,是形成肿瘤免疫微环境抑制的重要机制之一.有关Treg同肝癌的研究表明,Treg有可能成为肝癌免疫治疗的潜在靶点.     

细胞外基质在肝细胞性肝癌发生发展过程中的作用

肝细胞性肝癌(HCC)是我国常见的恶性肿瘤性疾病.近年来微环境对癌组织的影响受到重视,其中细胞外基质(ECM)作为HCC组织的重要微环境成分,在肿瘤发生发展过程中扮演着重要的角色,涉及肿瘤的生长、凋亡、耐药、侵袭、转移等.纤连蛋白(FN)、层粘连蛋白(LN)、透明质酸(HA)、胶原蛋白(COL)以及细胞外基质的硬度在H...     

Breaking through to the Other Side: Microenvironment Contributions to DCIS Initiation and Progression

Refinements in early detection, surgical and radiation therapy, and hormone receptor-targeted treatments have improved the survival rates for breast cancer patients. However, the ability to reliably identify which non-invasive lesions and localized tumors have the ability to progress and/or metastasize remains a major unmet need in the field. The current diagnostic and therapeutic strategies focus on intrinsic alterations within carcinoma cells that are closely associated with proliferation. However, substantial accumulating evidence has indicated that permissive changes in the stromal tissues surrounding the carcinoma play an integral role in breast cancer tumor initiation and progression. Numerous studies have suggested that the stromal environment surrounding ductal carcinoma in situ (DCIS) lesions actively contributes to enhancing tumor cell invasion and immune escape. This review will describe the current state of knowledge regarding the mechanisms through which the microenvironment interacts with DCIS lesions focusing on recent studies that describe the contributions of myoepithelial cells, fibroblasts and immune cells to invasion and subsequent progression. These mechanisms will be considered in the context of developing biomarkers for identifying lesions that will progress to invasive carcinoma and/or developing approaches for therapeutic intervention.     

肝癌免疫微环境与免疫治疗：研究进展与发展趋势

肝癌微环境主要由肿瘤相关巨噬细胞、肿瘤相关中性粒细胞、骨髓源性抑制细胞、肿瘤相关成纤维细胞和肿瘤浸润性淋巴细胞等细胞组分,以及细胞外基质、细胞因子等非细胞组分组成。免疫微环境在肝癌进程、免疫逃逸和治疗抵抗中发挥重要作用。近期,以调变炎症免疫微环境为基础的免疫治疗取得突破性进展,免疫疗法的出现为肝癌治疗提供了全新的选择,但仍存在客观缓解率较低、不良反应多和耐药问题。因此,深入研究微环境在肝癌发生发展中的作用及探索免疫治疗的未来发展趋势可提高现有治疗手段的应答率,对肝癌精准诊断与治疗有重要的理论价值和临床意义。     

High Expression of Proline-Rich Tyrosine Kinase2 is Associated with Poor Survival of Hepatocellular Carcinoma via Regulating Phosphatidylinositol 3-Kinase/AKT Pathway

Background

The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism.

Methods

Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation.

Results

Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K–AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells.

Conclusions

High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.

     

Matrix Metalloproteinases in Breast Cancer

Abstract: Matrix metalloproteinases (MMPs) represent a class of enzymes able to degrade numerous extracellular matrix macromolecules facilitating tumor invasion and metastasis. The principal MMPs involved in breast pathology are analyzed with their various roles and functions: gelatinases A and B, stromelysin-3, collagenase-3, and MT-MMP1 (membrane type MMP). In vivo and in vitro studies clearly demonstrate an important cooperation between tumor and stromal cells for the expression of these MMPs in breast carcinomas. The large expression of MMPs plead in favor of a major role of these enzymes in breast carcinoma progression and their detection may be used in some cases as a prognostic indicator. Studies now are in progress, directed toward the modulation of these MMPs and their inhibitors with new therapeutic agents to block tumoral invasion and metastasis due to these enzymes.?     

肝癌复发和转移的新理念

Cancer metastasis is considered as a complex process involving a series of sequential steps and a variety of molecalar signal transduction pathways.Tumor recurrence and metastasis are major obstacles for long-term survival of Liver cancer patients.Although the prognosis after recurrence and metastasis is dismal,the advancement of molecular researches of metastasis of liver cancer seems promising.In studies of origins of metastasis of liver cancer,the primary cancer cell and corresponding metastatic liver cancer cells share similar gene signature,which indicates that genes favoring metastasis progression are initiated in the primary tumors.The metastasis of liver cancer may be an early event in hepatic carcinogenesis and progression.Some molecular signatures have been developed to classify the metastatic potential of liver cancer.Furthermore,a variety of studies demonstrate that the tumor microenvironment instead of tumor cells plays a more important role in liver cancer metastasis.The pre-metastatic niche composed of non-tumoral cells may promote the cancer cell sedimentation and progression.The theory of cancer stem cell speculates that cancer stem cells were the real source of recurrent or metastatic tumors.Cancer stem cells will be one of the main targets of liver cancer treatment.The prevention and treatment of liver cancer recurrence or metastasis are quite difficult because liver cancer is resistant to traditional chemotherapy.Targeting the molecules involved in the metastasis of liver cancer WOuld be promising to cure those diseases.