Role of cancer-associated fibroblasts in the resistance to antitumor therapy,and their potential therapeutic mechanisms in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described.     

癌症相关成纤维细胞的异质性及其在靶向治疗中的应用

癌症相关成纤维细胞（cancer-associated fibroblasts,CAFs）是肿瘤微环境中最丰富和最关键的组成部分之一,不仅为肿瘤细胞提供物理支持,也在促进或延缓肿瘤发生发展方面起着关键作用。CAFs是一类高度丰富和异质性明显的间充质细胞系,包含大量不同表型和功能的细胞亚群,针对其异质性的靶向治疗也应运而生。本文阐述CAFs来源、表型和功能相关的异质性,以及在靶向治疗中应用的研究进展,以期提高对恶性肿瘤中CAFs的认识。     

Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth

Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) are a favorable prognosticator in surgically resected small cell lung cancer (SCLC). Here we explore whether CAFs expressing PDPN influence proliferation of SCLC cells. Compared with control group (SCLC cells co-cultured with CAFs-Ctrl), numbers of SCLC cells co-cultured with CAFs overexpressing PDPN were decreased. Suppression of PDPN expression by shRNA in CAFs resulted in increased numbers of SCLC cells. In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs. Thus CAFs expressing PDPN inhibit growth of SCLC cells, suggesting that CAFs expressing PDPN represent a tumor inhibitory stromal cell component in SCLC.     

In search of definitions: Cancer-associated fibroblasts and their markers

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.     

Molecular pathways and therapeutic targets in lung cancer

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.     

癌症相关成纤维细胞诱导的上皮间质转化增强肿瘤细胞干性的研究进展

在肿瘤细胞干性的获得和维持方面,肿瘤微环境扮演着十分重要的角色。作为其中数量最多的基质细胞,癌症相关成纤维细胞(cancer-associated fibroblasts,CAFs)可通过旁分泌信号和改变基质硬度的方式,诱导邻近的肿瘤细胞发生上皮-间质转化(epithelial-mesenchymal transition,EMT),使上皮来源细胞部分或完全地获得间充质表型。当细胞处于EMT进程中的某个过渡阶段时,即可被诱导表达干细胞表型,促进肿瘤的发生与进展。本文主要回顾了CAFs、EMT和肿瘤细胞干性相互之间的关系以及相关分子机制的研究,并尝试论述CAFs诱导肿瘤细胞的EMT增强其细胞干性。     

CAFs在胰腺癌肿瘤微环境中作用的研究进展

胰腺癌肿瘤微环境中癌相关成纤维细胞(cancer-associated fibroblasts, CAFs)具有促进胰腺癌组织增殖、侵袭、转移、血管生成、免疫抑制及耐药等作用,在胰腺癌的演变和进展中发挥了重要作用。由于CAFs的起源较多且具有表型和功能异质性,给靶向CAFs的抗肿瘤治疗带来了巨大挑战,但是探究CAFs与胰腺癌细胞的相互作用可以为日后靶向CAFs治疗胰腺癌提供帮助。本文将探究胰腺癌肿瘤微环境中CAFs的作用机制并对近些年来国内外有关CAFs对胰腺癌作用的相关文献进行综述。     

分子靶向治疗引领的肺癌病理诊断与分型进展

精准的病理诊断对于肺癌的分子靶向治疗尤为重要。为此,近年来在肺癌病理诊断及分型方面取得了许多重要进展。不同组织学类别的驱动基因谱及相应的分子靶向治疗靶点日渐明确,不同的组织学亚型和癌组织特殊形态特征可预测潜在的分子靶点,既往的大细胞癌诊断已为新标准所替代,大多数过去的大细胞癌已转归为腺癌或鳞癌,肺癌的异质性对其分子靶点的检测和结果的解释具有一定的影响,分子靶点的检测趋于多样化和更简便,突变特异性的免疫组化检测正成为可直接指导分子靶向治疗的常规方法。     

Intracellular signals of lung cancer cells as possible therapeutic targets

In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment; they have produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the development of lung cancers, a number of oncogenes are not covered by these advanced therapies. For the treatment of lung cancers, which is a group of heterogeneous diseases, persistent effort in developing individual therapies based on the respective causal genes is important. In addition, for the development of a novel therapy, identification of the lung epithelial stem cells and the origin cells of lung cancer, and understanding about candidate cancer stem cells in lung cancer tissues, their intracellular signaling pathways, and the mechanism of dysregulation of the pathways in cancer cells are extremely important. However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well‐known phenomenon. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies on origin and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies.     

Fibroblast growth factor-2, derived from cancer-associated fibroblasts,stimulates growth and progression of human breast cancer cells via FGFR1 signaling

Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA-MB-231 cells treated with the CAF-conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c-Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that fibroblast growth factor-2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal fibroblasts. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor-negative patients coexpressed FGF2 and FGFR1, whereas only 19% estrogen receptor-positive patients exhibited coexpression. CAF-stimulated MDA-MB-231 cell migration and invasiveness were abolished when FGF2-neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA-MB-231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2-induced cell migration and upregulation of Cyclin D1 were abolished by siRNA-mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote growth, migration and invasion of MDA-MB-231 cells via the paracrine FGF2-FGFR1 loop in the breast tumor microenvironment.     

c-Met在肺癌中的研究进展

c-Met是酪氨酸激酶受体的一种,由MET基因编码产生.肝细胞生长因子(HGF)作为c-Met唯一的天然配体,与其结合后激活相关下游通路如PI3K、MAPK和STAT 3等,参与肿瘤的增殖、迁移、侵袭等方面.c-Met主要激活形式包括有配体依赖的自分泌或旁分泌机制和非配体依赖机制等,许多恶性肿瘤包括肺癌在内均存在c-M...     

Heterogenous expression of endoglin marks advanced renal cancer with distinct tumor microenvironment fitness

Intratumoral heterogeneity, including in clear cell renal cell carcinoma, is a potential cause of drug resistance and metastatic cancer progression. We specified the heterogeneous population marked by endoglin (also known as CD105) in a preclinical model of clear cell renal cell carcinoma progression. Highly malignant derivatives of human clear cell renal cell carcinoma OS-RC-2 cells were established as OS5Ks by serial orthotopic inoculation in our previous study. Expression of both ENG (encoding endoglin) mRNA and protein were heterogeneously upregulated in OS5Ks, and the endoglin-positive (ENG⁺) population exhibited growth dependency on endoglin in anchorage-independent cultures. Despite the function of endoglin as a type III receptor, transforming growth factor β and bone morphogenetic protein-9 signaling were unlikely to contribute to the proliferative phenotype. Although endoglin has been proposed as a marker for renal cancer-initiating cells, the OS5K-3 ENG⁺ population did not enrich other reported cancer-initiating cell markers or differentiate into the ENG^– population. Mouse tumor inoculation models revealed that the tumor-forming capabilities of OS5K-3 ENG⁺ and ENG^– cells in vivo were highly dependent on the microenvironment, with the renal microenvironment most preferable to ENG⁺ cells. In conclusion, the renal microenvironment, rather than the hypothesized ENG⁺ cell-centered hierarchy, maintains cellular heterogeneity in clear cell renal cell carcinoma. Therefore, the effect of the microenvironment should be considered when evaluating the proliferative capability of renal cancer cells in the experimental settings.     

4th international conference on tumor progression and therapeutic resistance: meeting report

The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field.     

Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer

The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor-suppressive function of miR-21 in in vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.     

Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs – allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.     

Increased expression of immunosuppressive molecules on intratumoral and circulating regulatory T cells in non-small-cell lung cancer patients

The expression patterns of immunosuppressive molecules on regulatory T (Treg) cells have not been elucidated in non-small-cell lung cancer (NSCLC) patients. In this study, a total of 88 patients including 53 patients with NSCLC, 17 patients with lung non-malignant diseases, and 18 healthy volunteers were enrolled. Increased number of total CD4⁺CD25⁺FoxP3⁺ Treg cells and elevated expressions on the surface of several inhibitory molecules including CTLA-4, LAG-3 and PD-1 have been observed in the peripheral blood of NSCLC patients. We found that intratumoral Treg cells from NSCLC patients express the highest levels of co-inhibitory molecules compared to Treg cells isolated from tumor adjacent tissues or from peripheral blood of cancer patients, which is in consistent with the enhanced immunosuppressive function of these co-inhibitory molecules. Moreover, the number of Treg cells and their functional surface molecules increased during the progression of lung cancer. Elevated plasma levels of TGF-β and IL-10 in NSCLC patients were also observed in NSCLC patients compared to that in healthy volunteers. Our findings further support the role of Treg cells in the tumor microenvironments in NSCLC patients.     

EGFR-TKI靶向治疗肺癌的临床效果及对患者肿瘤标志物水平、肺功能指标的影响

目的观察表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)靶向治疗肺癌的临床效果及对患者肿瘤标志物水平、肺功能指标的影响。方法根据治疗方式的不同将70例肺癌患者分为对照组和观察组,每组35例。对照组患者接受传统的化疗方案(紫杉醇+顺铂静脉化疗)进行治疗,观察组患者在对照组治疗方案的基础上接受EGFR-TKI靶向治疗。观察两组患者的总缓解率、肿瘤标志物水平、肺功能指标和不良反应发生情况。结果两组患者的总缓解率比较,差异无统计学意义(P﹥0.05)。治疗后,两组患者的神经元特异性烯醇化酶(NSE)、细胞角质蛋白19片段抗原21-1(CYFRA21-1)和糖类抗原19-9(CA19-9)水平均低于本组治疗前(P﹤0.05),且观察组患者的NSE、CYFRA21-1和CA19-9水平均明显低于对照组患者(P﹤0.01)。对照组患者的不良反应总发生率为25.71%,观察组患者的不良反应总发生率为11.43%,两组比较,差异无统计学意义(P﹥0.05)。结论EGFR-TKI靶向治疗肺癌的临床疗效较好,可明显降低肺癌患者的肿瘤标志物水平,安全可靠,具有良好的临床应用价值。