Lung cancer is one of the most lethal tumors in the world with a 5-year overall survival rate of less than 20%, mainly including lung adenocarcinoma (LUAD). Tumor microenvironment (TME) has become a new research focus in the treatment of lung cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. The various cellular components exert a different role in apoptosis, metastasis, or proliferation of lung cancer cells through different pathways, thus contributing to the treatment of adenocarcinoma and potentially facilitating novel therapeutic methods. This review summarizes the research progress on different cellular components with cell-cell interactions in the TME of LUAD, along with their corresponding drug candidates, suggesting that targeting cellular components in the TME of LUAD holds great promise for future theraputic development.
Humans ; Tumor Microenvironment/drug effects* ; Adenocarcinoma of Lung/drug therapy* ; Lung Neoplasms/pathology* ; Adenocarcinoma/metabolism* ; Animals ; Apoptosis/physiology*

The incidence and mortality rates of lung cancer remain high, making it the leading cause of cancer-related deaths. In women, the predominant histological subtype is lung adenocarcinoma, commonly associated with epidermal growth factor receptor (EGFR) mutations, and EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can significantly improve patient prognosis. Metastasis of primary lung cancer to the endometrium is extremely rare and is often misdiagnosed as a primary reproductive system tumor, and its occurrence indicates poor prognosis. This article reports a case of an advanced lung adenocarcinoma patient with EGFR mutation, who developed abnormal vaginal bleeding after EGFR-TKIs treatment failure, and biopsy confirmed endometrial metastasis. A review of similar cases is also presented.
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Humans ; Female ; ErbB Receptors/metabolism* ; Endometrial Neoplasms/genetics* ; Lung Neoplasms/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Adenocarcinoma of Lung/drug therapy* ; Treatment Failure ; Middle Aged ; Adenocarcinoma/genetics*

In recent years, the number of advanced non-small cell lung cancer (NSCLC) patients has gradually increased, and the treatment methods have also been significantly increased. However, there are no standard treatment plans at home and abroad for third-line and above patients who are refractory to targeted therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) or chemotherapy. The clinical treatment effect is also not satisfactory. Anlotinib is a novel TKI targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit. ALTER0303 trail, phase III study has demonstrated that Anlotinib significantly prolonged overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients as 3rd line treatment.Here we report a case of advanced lung adenocarcinoma harboring KRAS mutation treated with Anlotinib.
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Adenocarcinoma ; drug therapy ; enzymology ; genetics ; pathology ; Adenocarcinoma of Lung ; Aged ; Antineoplastic Agents ; therapeutic use ; Humans ; Indoles ; therapeutic use ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; pathology ; Male ; Mutation ; Proto-Oncogene Proteins p21(ras) ; genetics ; metabolism ; Quinolines ; therapeutic use

BACKGROUND: There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or Kelch-like ECH-associated protein 1 (Keap1) in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different "driver gene" is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients. METHODS: Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. RESULTS: The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P<0.05), but not with age, smoking, differentiation and subtype of lung adenocarcinoma (P>0.05). The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05). The progression -free survival (PFS) and overall survival (OS) of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05). Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05). CONCLUSIONS The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.
Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; Adenocarcinoma of Lung ; Adult ; Aged ; Aged, 80 and over ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Kelch-Like ECH-Associated Protein 1 ; genetics ; metabolism ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Mutation ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Neoplasm Staging ; Protein Kinase Inhibitors ; therapeutic use ; Young Adult

Adenocarcinoma ; complications ; drug therapy ; metabolism ; Aged ; Antineoplastic Agents ; therapeutic use ; Fusion Proteins, bcr-abl ; metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; diagnosis ; etiology ; metabolism ; Male ; Organoplatinum Compounds ; therapeutic use ; Stomach Neoplasms ; drug therapy ; metabolism

PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
Adenocarcinoma/drug therapy/*genetics ; Cell Line, Tumor ; Cetuximab/pharmacology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Epidermal Growth Factor/metabolism/*pharmacology ; *Gene Rearrangement ; Hepatocyte Growth Factor/*pharmacology ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/*genetics ; MAP Kinase Signaling System ; *Mutation ; Niacinamide/analogs & derivatives/pharmacology ; Phenylurea Compounds/pharmacology ; Piperidines/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; RNA, Small Interfering/pharmacology ; Receptor, Epidermal Growth Factor/genetics/metabolism ; Signal Transduction/drug effects ; fms-Like Tyrosine Kinase 3/metabolism

PURPOSE: Docetaxel-based chemotherapy (DTX) improves overall survival (OS) of men with metastatic castration-resistant prostate cancer (mCRPC). Considering the potential existence of androgen receptors that remain active at this stage, we aimed to assess the impact of the combined use of androgen deprivation therapy (ADT) with DTX for mCRPC. MATERIALS AND METHODS: We performed a single-institutional retrospective analysis of patients with mCRPC who received either DTX alone (DTX group, n=21) or concurrent DTX and ADT (DTX+ADT group, n=26) between August 2006 and February 2014. All patients received DTX doses of 75 mg/m2 every three weeks for at least three cycles. In the DTX+ADT group, all patients used luteinizing hormone releasing hormone agonist continuously as a concurrent ADT. RESULTS: The median follow-up period was 24.0 months (interquartile range 12.0-37.0) for the entire cohort. The median radiographic progression-free survival (rPFS) was 9.0 months and 6.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.036). On multivariable Cox regression analysis, concurrent administration of ADT was the only significant predictor of rPFS [hazard ratio (HR)=0.525, 95% confidence intervals (CI) 0.284-0.970, p=0.040]. The median OS was 42.0 and 38.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.796). On multivariable analysis, hemoglobin level at the time of DTX initiation was associated with OS (HR=0.532, 95% CI 0.381-0.744, p<0.001). CONCLUSION: In chemotherapy-naive patients with mCRPC, the combined use of ADT with DTX improved rPFS. Our result suggests that the concurrent administration of ADT and DTX is superior to DTX alone.
Adenocarcinoma/blood/*drug therapy/secondary ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Disease-Free Survival ; Gonadotropin-Releasing Hormone/administration & dosage/agonists ; Hemoglobins/metabolism ; Humans ; Male ; Middle Aged ; Prostatic Neoplasms, Castration-Resistant/blood/*drug therapy/pathology ; Retrospective Studies ; Survival Rate ; Taxoids/administration & dosage

OBJECTIVETo explore the apoptosis mechanism of Wenxia Changfu Formula (, WCF) in reversing drug resistance of lung cancer in vivo.

METHODSThirty model mice were randomly assigned to three groups: control group, cisplatin (CDDP) group, and WCF group. A transplanted tumor model of lung adenocarcinoma was established in all groups. Mice in the WCF group received intragastric administration of WCF (0.2 mL/10 g body weight) everyday in addition to CDDP intraperitoneally (5 mg/kg body weight) twice a week. The mice in the CDDP group received CDDP intraperitoneally (5 mg/kg body weight) twice a week, while the control group received normal saline intraperitoneally (0.2 mL/10 g body weight) everyday. The weight of the nude mice and respective tumors, tumor volume and tumor-inhibiting rate were measured. Electron microscopy was used to observe the existence of apoptosis body. Apoptosis index (AI) was detected by TdT-mediated dUTP nick end labeling staining. The expression of Fas and FasL mRNA was investigated by reverse transcription polymerase chain reaction, while immunohistochemistry was applied to detect the protein expression of Fas and FasL, caspase-3 and caspase-activated DNase (CAD), respectively.

RESULTSCompared with CDDP group and control group, WCF could significantly reduce the tumor volume from the 19th day and alleviate the tumor weight (P <0.05), and the apoptosis body was found in tumor cells in the WCF group. WCF could also enhance the level of AI, up-regulate the expression of caspase apoptosis pathway related protein caspase-3 and CAD, as well as the expression of Fas, FasL mRNA and protein (P <0.05).

CONCLUSIONWCF could improve the sensitivity of tumor cells to CDDP and reverse the drug resistance by inducing the apoptosis.

Adenocarcinoma ; drug therapy ; pathology ; Animals ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; Cisplatin ; pharmacology ; Drug Resistance, Neoplasm ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Fas Ligand Protein ; genetics ; metabolism ; Female ; Fluorescent Antibody Technique ; Humans ; In Situ Nick-End Labeling ; Lung Neoplasms ; drug therapy ; pathology ; Mice, Nude ; RNA, Messenger ; genetics ; metabolism ; Tumor Burden ; drug effects ; Xenograft Model Antitumor Assays ; fas Receptor ; metabolism

Clear cell carcinoma (CCC) of the ovary is known to show poorer sensitivity to chemotherapeutic agents and to be associated with a worse prognosis than the more common serous adenocarcinoma or endometrioid adenocarcinoma. To improve the survival of patients with ovarian CCC, the deeper understanding of the mechanism of CCC carcinogenesis as well as the efforts to develop novel treatment strategies in the setting of both front-line treatment and salvage treatment for recurrent disease are needed. In this presentation, we first summarize the mechanism responsible for carcinogenesis. Then, we highlight the promising therapeutic targets in ovarian CCC and provide information on the novel agents which inhibit these molecular targets. Moreover, we discuss on the cytotoxic anti-cancer agents that can be best combined with targeted agents in the treatment of ovarian CCC.
Adenocarcinoma, Clear Cell/drug therapy/*etiology/metabolism ; Antineoplastic Agents/therapeutic use ; Female ; Forecasting ; Humans ; Neoplasm Recurrence, Local/prevention & control ; Ovarian Neoplasms/drug therapy/*etiology/metabolism

OBJECTIVETo investigate the predictive value of P53, Ki-67, HER2 protein detection in neoadjuvant chemotherapy for adenocarcinoma of gastroesophageal junction (AGEJ).

METHODSPreoperative biopsy specimens and clinical data of 72 patients of locally advanced Siewert II AGEJ between June 2010 and December 2013 were reviewed. All the patients received SOX scheme neoadjuvant chemotherapy, and were divided into effective group (complete response plus partial response) and ineffective group (stable disease plus progressive disease). Expressions of above 3 proteins were detected by immunohistochemistry in all the patients before neoadjuvant chemotherapy. The relationship between various proteins and efficacy of chemotherapy was analyzed by univariate and logistic multivariate regression analyses.

RESULTSAll the 72 patients successfully completed 2 cycles of SOX neoadjuvant chemotherapy, among them, 5 cases (6.9%) with complete response, 30 cases (41.7%) with partial response, 31 cases (43.1%) with stable disease, 6 cases (8.3%) with progressive disease, including 35 cases in effective group and 37 cases in ineffective group. Compared with ineffective group, the positive expression rate of P53 was significantly reduced (25.0% vs. 45.9%, P=0.020), and that of Ki-67 significantly increased (77.1% vs. 43.2%, P=0.003), however, there was no significant difference in the expression rate of HER2 between the two groups (P>0.05). Multivariate analysis showed that Ki-67 was the independent predictive factor for the efficacy of neoadjuvant chemotherapy (P=0.015). Spearman rank correlation showed that Ki-67 expression was positively correlated with HER2 expression (r=0.259, P=0.028), but P53 expression was not correlated with Ki-67 or HER2 (r=0.140, 0.042, P=0.240, 0.725, respectively).

CONCLUSIONSSOX neoadjuvant chemotherapy is safe and effective for AGEJ, especially for patients with depressed expression of P53 and elevated expression of Ki-67, which both may be used as reference for the prediction of chemotherapy efficacy. There is no correlation between P53 and Ki67 proteins, so combined detection may improve the predictive value.

Adenocarcinoma ; diagnosis ; drug therapy ; Esophageal Neoplasms ; diagnosis ; drug therapy ; Esophagogastric Junction ; pathology ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Neoadjuvant Therapy ; Receptor, ErbB-2 ; metabolism ; Remission Induction ; Tumor Suppressor Protein p53 ; metabolism