ABSTRACT
A superior pulmonary sulcus tumor, also known as a Pancoast tumor, invades tissues or organs at the entrance of the thorax, such as the brachial plexus, upper ribs, vertebrae, subclavian vessels and stellate ganglia. Induction concurrent chemoradiotherapy followed by radical surgical resection is the preferred treatment. The present study reported the case of a 52-year-old male who presented at Hubei Cancer Hospital, Tongji Medical College (Wuhan, Hubei) with left chest pain and an abnormal chest computed tomography scan showing a mass of 81x43 mm in the left upper chest wall that invaded the first, second and third anterior ribs. Biopsy of the mass showed stage cT4N0M0, IIIA, poorly differentiated adenocarcinoma and epidermal growth factor receptor+. The patient was treated by induction chemotherapy and targeted therapy, which was followed by surgical resection of the left upper lobe and the affected chest wall via the transmanubrial approach. The targeted therapy with almonertinib was continued postoperatively. To date, no disease recurrence has been detected during the 4 months follow-up.
ABSTRACT
Estrogen classically drives lung cancer development via estrogen receptor ß (ERß). However, fulvestrant, an anti-estrogen-based endocrine therapeutic treatment, shows limited effects for non-small cell lung cancer (NSCLC) in phase II clinical trials. G protein-coupled estrogen receptor (GPER), a third estrogen receptor that binds to estrogen, has been found to be activated by fulvestrant, stimulating the progression of breast, endometrial, and ovarian cancers. We here demonstrated that cytoplasm-GPER (cGPER) (80.49 %) and nucleus-GPER (53.05 %) were detected by immunohistochemical analysis in NSCLC samples. cGPER expression was related to stages IIIA-IV, lymph node metastasis, and poorly differentiated NSCLC. Selective agonist G1 and 17ß-estradiol (E2) promoted the GPER-mediated proliferation, invasion, and migration of NSCLC cells. Additionally, in vitro administration of E2 and G1 increased the number of tumor nodules, tumor grade, and tumor index in a urethane-induced adenocarcinoma model. Importantly, the pro-tumorigenic effects of GPER induced by E2 were significantly reduced by co-administering the GPER inhibitor G15 and the ERß inhibitor fulvestrant, as compared to administering fulvestrant alone both in vitro and in vivo. Moreover, the phosphorylation of MAPK and Akt was involved in E2/G1-induced GPER activation. In conclusion, our results indicated that a pro-tumor function of GPER exists that mediated E2-/G1-dependent NSCLC progression and showed better efficiency regarding the co-targeting of GPER and ERß, providing a rationale for further investigation of anti-estrogen clinical therapy.
Subject(s)
Adenocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Cyclopentanes/pharmacology , Estradiol/analogs & derivatives , Lung Neoplasms/pathology , Quinolines/pharmacology , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Adenocarcinoma/chemically induced , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Aged , Animals , Apoptosis/drug effects , Blotting, Western , Carcinogens/toxicity , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Adhesion/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Progression , Estradiol/pharmacology , Estrogen Receptor Antagonists/pharmacology , Female , Fulvestrant , Humans , Immunoenzyme Techniques , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lymphatic Metastasis , Male , Mice , Middle Aged , Neoplasm Staging , Phosphorylation/drug effects , Prognosis , RNA, Small Interfering/genetics , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/genetics , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Tissue Array Analysis , Tumor Cells, Cultured , Urethane/toxicity , Xenograft Model Antitumor AssaysABSTRACT
Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer pathogenesis and progression. While its signaling pathway is an interesting therapeutic target, recent clinical trials have exhibited limited effects; however, significant crosstalks between IGF- 1R and other signaling pathways have garnered increasing attention. These complex networks include interactions between IGF-1R and receptor tyrosine kinases (RTKs), including insulin receptor (IR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), mesenchymal-epithelial transition factor (MET), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Furthermore, IGF-1R also is related to steroid hormones, including estrogen receptors alpha and beta (ER! and ER"), androgen receptor (AR), and progesterone receptor (PR). Cumulatively, actions of crosstalk between IGF-1R, and RTKs/steroid hormones promote tumorigenesis, as demonstrated by the effectiveness of recently proposed therapeutic strategies. These therapeutic strategies, primarily pertaining to crosstalk-cotargeting, exhibited notable advantages in overcoming resistance to conventional chemotherapy and conventional endocrine therapy. Furthermore, these techniques offer benefits beyond the limited effects of single- agent targeting previously reported. Thus, the role of crosstalk between IGF-1R and RTKs/steroid hormones, including strategies to block these pathways in combination with recent development in this field, were reviewed and the potential future cancer therapeutics suggested by this rationale were considered.
Subject(s)
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/metabolism , Receptor Cross-Talk , Receptor, IGF Type 1/metabolism , Signal Transduction , Antineoplastic Agents/pharmacology , Gonadal Steroid Hormones/metabolism , Humans , Models, Biological , Neoplasms/pathology , Receptor Cross-Talk/drug effects , Receptor, IGF Type 1/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17ß-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERß, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERß, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ERß, ERß2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ERß, p-ERß, ERß2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERß1, ERß2 and IGF-1R play important roles.
