title: In the hunt for therapeutic targets: mimicking the growth, metastasis, and stromal associations of early-stage lung cancer using a novel orthotopic animal model.
abstract: BACKGROUND
  The existing shortage of animal models that properly mimic the progression of early-stage human lung cancer from a solitary confined tumor to an invasive metastatic disease hinders accurate characterization of key interactions between lung cancer cells and their stroma. We herein describe a novel orthotopic animal model that addresses these concerns and consequently serves as an attractive platform to study tumor-stromal cell interactions under conditions that reflect early-stage lung cancer.
  
  
  METHODS
  Unlike previous methodologies, we directly injected small numbers of human or murine lung cancer cells into murine's left lung and longitudinally monitored disease progression. Next, we used green fluorescent protein-tagged tumor cells and immuno-fluorescent staining to determine the tumor's microanatomic distribution and to look for tumor-infiltrating immune cells and stromal cells. Finally, we compared chemokine gene expression patterns in the tumor and lung microenvironment.
  
  
  RESULTS
  We successfully generated a solitary pulmonary nodule surrounded by normal lung parenchyma that grew locally and spread distally over time. Notably, we found that both fibroblasts and leukocytes are recruited to the tumor's margins and that distinct myeloid cell attracting and CCR2-binding chemokines are specifically induced in the tumor microenvironment.
  
  
  CONCLUSIONS
  Our orthotopic lung cancer model closely mimics the pathologic sequence of events that characterizes early-stage human lung cancer propagation. It further introduces new means to monitor tumor-stromal cell interactions and offers unique opportunities to test therapeutic targets under conditions that reflect early-stage lung cancer. We argue that for such purposes our model is superior to lung cancer models that are based either on genetic induction of epithelial transformation or on ectopic transplantation of malignant cells.
authors: *Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel; †Laboratory for Surgical Research, Hadassah University Hospital, Jerusalem, Israel; ‡Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and §Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel.
authors: Ido D
authors: ID
authors: Weiss
authors: Ezra
authors: E
authors: Ella
authors: Omri
authors: O
authors: Dominsky
authors: Yoav
authors: Y
authors: Smith
authors: Michal
authors: M
authors: Abraham
authors: Hanna
authors: H
authors: Wald
authors: Zippora
authors: Z
authors: Shlomai
authors: Gideon
authors: G
authors: Zamir
authors: Sara W
authors: SW
authors: Feigelson
authors: Elias
authors: E
authors: Shezen
authors: Amir
authors: A
authors: Bar-Shai
authors: Ronen
authors: R
authors: Alon
authors: Uzi
authors: U
authors: Izhar
authors: Amnon
authors: A
authors: Peled
authors: Oz M
authors: OM
authors: Shapira
authors: Ori
authors: O
authors: Wald
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology* / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays