A novel orthotopic implantation model of human esophageal carcinoma in nude rats: CD44H mediates cancer cell invasionin vitro andin vivo

Abstract

A new orthotopic esophageal cancer model was developed by implanting fragments of xenografts of T.T human esophageal squamous carcinoma cells into the cervical esophagus of athymic rats. The rats had symptoms analogous to the human clinical course such as respiratory distress, dysphagia, vomiting of blood, or Horner syndrome, followed by death resulting from suffocation. Microscopic metastases of lymph node were observed around the tumor in 3 of 18 rats. A new cell line (T.T-1) was established from these metastases. Flow cytometry showed that T.T-1 and T.T parental cells had nearly the same surface levels of ␤1-integrin, ␣2-integrin, ␣3-integrin and E-cadherin, and no expression of CD44v3, CD44v6 and ␣5-integrin. T.T-1 cells had a higher level of CD44H, however, and a greater binding efficiency to the extracellular matrix components; laminin, type IV collagen, hyaluronic acid, and fibronectin than T. Key words: esophageal cancer; orthotopic implantation; CD44; adhesion; invasionEsophageal cancer is one of the most lethal cancers. By the time it is diagnosed it is often at an advanced stage that is characterized by lymph node metastases and invasion to adjacent organs. Distant lymph node metastasis appears relatively early in patients with esophageal cancer because of anatomical characteristics that more lymphatic vessels run longitudinally than horizontally in the esophageal submucosal layer. Direct invasion of esophageal tumor cells into adjacent organs, especially the trachea or aorta, makes a complete resection impossible. The 5-year survival is around 30% to 50%, even after a complete resection with lymph node dissection. [1][2][3][4][5] Other treatment strategies such as chemoradiotherapy have not been definitely demonstrated to have curative effectiveness. 6,7 It seems, therefore, that an important preclinical goal is to elucidate the mechanisms involved in the invasion and metastasis of esophageal cancer cells and to search for novel treatment strategies in vivo.Most athymic animal models of human cancers have been produced by subcutaneous transplantations. Tumor cells rarely metastasize in these types of models, 8 even when highly aggressive tumors have served as the source of xenografts. 9 Several athymic mouse models of human pancreatic cancer using orthotopic implantation have resulted in invasive local tumor growth and subsequent lymph node and hepatic metastases. 10,11 Other orthotopic athymic mouse models have also been reported for human cancers such as colon, pancreas, lung, stomach, liver, kidney, ovary, prostate, urinary bladder, breast, and head and neck. 12-21 Thus, an orthotopic athymic animal model would seem to be the most useful for studying esophageal cancer cell invasion and metastasis. No such model, however, has previously been reported. Our present study was undertaken to develop this type of model. We have successfully produced transplants of xenografts of T.T human esophageal squamous cell carcinoma cells onto the esophagus of athymic rats. A new tumor cell line was developed from...

Comprehensive spectral endoscopy of topically applied SERS nanoparticles in the rat esophagus

“…Therefore, we are developing a device to image the rat esophagus. In the future, this device may be used to investigate the molecular changes associated with tumor progression in rat models such as a chemically induced model of esophageal cancer [38,39] as well as an orthotopic xenograft model [40].…”

Adenoviral-Based Immunotherapy Provides Local Disease Control in an Orthotopic Murine Model of Esophageal Cancer

“…Nevertheless, tumors in this model have been slow to develop and appear with limited consistency (in less than 25% of mice). A third model involves explantation of esophageal cancer xenografts into immunodeficient mice (13, 14, 41, 42). Although this model produces consistent results, conclusions drawn from experimentation in immunodeficient hosts are not generalizable to the human population.…”

“…Most experiments have been performed using human esophageal cancer cell lines in immunodeficient mice or have used tumor lines from alternative disease types and extrapolated the results to esophageal cancer (12-14). In response, our group was the first to develop a syngeneic murine model of esophageal cancer (15, 16), which we used to demonstrate the effectiveness of neoadjuvant in situ gene-mediated cytotoxic immunotherapy.…”

Cellular and Molecular Biology of Esophageal Cancer

“…Different approaches have been applied but many of these have some shortcomings. The establishment of these orthotopic models needs to involve radiological guidance (magnetic resonance imaging and fl uorescence imaging) so the cancer and the metastases can be visualized in real time [ 82 ]. In addition, pathological examination is important to clarify the histological typing, microscopic location, and the microenvironment of the cancer in the animal [ 83 ].…”