Drug resistance is of great concern in cancer treatment because most effective drugs are limited by the development of resistance following some periods of therapeutic administration. The tumor microenvironment (TME), which includes various types of cells and extracellular components, mediates tumor progression and affects treatment efficacy. TME-mediated drug resistance is associated with tumor cells and their pericellular matrix. Noninherent-adaptive drug resistance refers to a non-cell-autonomous mechanism in which the resistance lies in the treatment process rather than genetic or epigenetic changes, and this mechanism is closely related to the TME. A new concept is therefore proposed in which tumor cell resistance to targeted therapy may be due to non-cell-autonomous mechanisms. However, knowledge of non-cell-autonomous mechanisms of resistance to different treatments is not comprehensive. In this review, we outlined TME factors and molecular events involved in the regulation of non-cell-autonomous resistance of cancer, summarized how the TME contributes to non-cell-autonomous drug resistance in different types of antineoplastic treatment, and discussed the novel strategies to investigate and overcome the non-cell-autonomous mechanism of cancer non-cell-autonomous resistance.

Osteosarcoma (OS) is a common primary malignant bone tumor with high morbidity and mortality in children and young adults. How to improve poor prognosis of OS due to resistance to chemotherapy remains a challenge. Recently, growing findings show activation of mammalian target of rapamycin (mTOR), is associated with OS cell growth, proliferation, metastasis. Targeting mTOR may be a promising therapeutic approach for treating OS. This review summarizes the roles of mTOR pathway in OS and present research status of mTOR inhibitors in the context of OS. In addition, we have attempted to discuss how to design a better treatment project for OS by combining mTOR inhibitor with other drugs.

Down-regulation of β-amyrin synthase gene expression by RNA interference led to reduced levels of β-amyrin and oleanane-type ginsenoside as well as up-regulation of dammarane-type ginsenoside level. In the biosynthetic pathway of ginsenosides, β-amyrin synthase catalyzes the reaction from oxidosqualene to β-amyrin, the proposed aglycone of oleanane-type saponins. Here, RNAi was employed to evaluate the role of this gene in ginsenoside biosynthesis of Panax ginseng hairy roots. The results showed that RNAi-mediated down-regulation of this gene led to reduced levels of β-amyrin and oleanane-type ginsenoside Ro as well as increased level of total ginsenosides, indicating an important role of this gene in biosynthesis of ginsenoside. Expression of key genes involved in dammarane-type ginsenoside including genes of dammarenediol synthase and protopanaxadiol and protopanaxatriol synthases were up-regulated in RNAi lines. While expression of squalene synthase genes was not significantly changed, β-amyrin oxidase gene was down-regulated. This work will be helpful for further understanding ginsenoside biosynthesis pathway.

Lung cancer is the most frequently diagnosed cancer and the main cause of cancer death in the world. X-box binding protein 1 (XBP1), which is an important transcription factor involved in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, might act as a potent oncogenic protein in the processes of tumorigenesis, tumor proliferation and metastasis in various cancers. However, the clinical significance and pathological role of XBP1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the expression of XBP1s protein in the 104 NSCLC tumor tissues and matched adjacent normal lung tissues (ANLT) by Immunohistochemical (IHC), and we found overexpressed XBP1s protein was associated with NSCLC TNM stages, lymph node metastasis and poor prognosis. The further gain-and loss-of-function experiments indicated overexpression of XBP1s protein promoted cell invasion, migration and metastasis both in vitro and in vivo. Further study showed XBP1s protein could upregulate insulin-like growth factor binding protein-3 (IGFBP3) expression, and regulated NSCLC cells invasion and metastasis by regulating IGFBP3. Taken together, XBP1s protein is markedly overexpressed in NSCLC and serves as an oncogene that play a critical role in NSCLC tumorigenesis and development. Importantly, XBP1s protein might not only be a potential biomarker for metastasis and prognosis but also a potential therapeutic target in NSCLC.