Tumor reactive stroma in cholangiocarcinoma:The fuel behind cancer aggressiveness

Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma(TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS(myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors(cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix(ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells(as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.

细胞外基质与肿瘤相关成纤维细胞

肿瘤的发生发展是一个肿瘤细胞与其微环境相互促进,共同演化的动态过程.实体肿瘤的发生发展过程伴随细胞外基质的过量沉积及其组织形式的异常以及成纤维细胞的活化和富集.细胞外基质与肿瘤相关成纤维细胞不仅是实体肿瘤的重要病理特征,同时也是恶性肿瘤发展的重要驱动力量.细胞外基质与肿瘤相关成纤维细胞通过多种机制促进了肿瘤的发生、发展和转移.针对细胞外基质与肿瘤相关成纤维细胞进行肿瘤治疗,可以为肿瘤的临床治疗提供新的思路.

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness.Although significant efforts have been made to model desmoplastic PDAC,existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC.Here,two major components in desmoplastic pancreatic matrices,hyaluronic acid-and gelatin-based hydrogels,are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts(CAF).Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation.Higher expression levels of markers associated with proliferation,epithelial to mesenchymal transition,mechanotransduction,and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels,while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1(TGF-β1).The proposed multicellular pancreatic tumor model,in combination with proper mechanical properties and TGF-β1 supplement,makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors,which could be potentially applicable for realizing personalized medicine and drug testing applications.

Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma

Progression of cancer is often associated with interactions between cancer cells and extracellular matrix(ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan(HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma(PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.

Recent advances in immunotherapy for pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan and oxaliplatin),and gemcitabine plus nab-paclitaxel.Despite the improvement noted in these trials,PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance.The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments.Therapeutic vaccines,combination treatments,adoptive T cell transfer,as well as immunomodulators are being explored.With the emerging use of immunotherapy and immunomodulators,the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC.Overall,results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.

Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.

结缔组织生成和肿瘤

肿瘤的发生并不只是由肿瘤细胞本身恶化引起的,肿瘤基质也发挥了非常重要的作用,肿瘤发生是肿瘤细胞和围绕它的肿瘤基质相互作用的产物。肿瘤细胞可以通过各种途径激活与其相邻的间质,促进成纤维细胞的增生、细胞外基质的沉积、免疫细胞浸润和血管生成,这种现象被称为结缔组织生成。结缔组织生成形成了一个支持肿瘤发展的微环境,通过多种途径促进了肿瘤的发生、发展和转移。针对结缔组织生成进行肿瘤治疗可以为肿瘤的临床治疗提供新的思路。