Human colorectal cancer : experimental staging and therapeutics

• Colorectal cancer is the third most common cause of death in cancer worldwide and approximately one million individuals are diagnosed yearly. Surgery is the primary cure, and if that s not feasible, only palliative therapy remains. Colorectal cancer disseminates into peritumoral lymphatic vessels and further into the regional lymph nodes. In the lymph nodes the tumor cells may arrest and establish a metastasis, or bypass into the systemic circulation through lymphovenous shunts. A tumor may shed millions of cells daily, but fewer than 0.1% reside in organs. Metastases to regional lymph nodes or more distant organs are of crucial prognostic importance in colorectal cancer and constitute the largest clinical challenge. The sentinel node is the first draining lymph node to a tumor and may therefore reflect the tumor status of the entire lymphatic field. We have demonstrated the feasibility of identifying the sentinel node in colon cancer with an accuracy of 100% in 30 patients, and in 93.8% the sentinel node was diagnostic for lymph node metastases. The false negative rate in our first study was 16.7%. At follow up after at least 30 months, only patients with lymph node metastases at surgery had died from colon cancer. We believe that the sentinel node technique may improve staging in colorectal cancer, leading to more patients receiving correct prognosis and follow-up. When tumor cells are arrested in regional lymph nodes they are exposed for the immune system, which has the capacity of eliminating tumor cells. The first place of encounter is the sentinel node. We have studied the immunological function of sentinel node derived lymphocytes in vitro. The lymphocytes from non-metastasized sentinel nodes proliferated dose-dependently upon stimulation with tumor cells, interleukin-2 and antigen presenting cells. Lymphocytes from metastasized sentinel nodes and tumor infiltrating lymphocytes were normally unresponsive to stimuli. We have demonstrated the presence of tumor-reactive lymphocytes with a capacity of killing tumor cells in sentinel nodes. Despite efficient surgical interventions and the use of modern adjuvant therapy, about half of the colorectal cancer patients will die of disseminated disease within five years of diagnosis. Clearly, there is a need for improved ways of treatment. In our 3rd paper we used in vitro expanded sentinel node derived lymphocytes as adoptive immunotherapy. Following the principles outlined in the 2nd paper, we multiplied tumor-reactive lymphocytes, mainly of T-helper type 1, to high numbers, before giving them back to the patients as an autologous blood transfusion. In all studied sixteen patients we managed to perform immunotherapy after on average 36 days of expansion in vitro. The therapy had no side-effects. All patients responded to the therapy. Out of the nine patients in the study having Dukes´ D disease, four patients achieved complete response with regress of metastases, and two patients had partial responses. The remaining ten patients displayed stable disease. None of the patients in the study received any regular chemotherapy regimens after the immunotherapy. To our knowledge, this is the first study showing therapeutic effects related to sentinel nodes. The sentinel node technique is established in staging for malignant melanoma and breast cancer and has been evaluated in several other malignancies. Probably, most solid tumors disseminate through the lymphatics. Since it is proven that metastases have the capacity to metastasize and to induce tumoral lymphangiogenesis, we wanted to evaluate the lymphatic drainage from metastases. We identified metastases-draining lymph nodes in all nineteen investigated patients and we named these nodes metinel nodes . Analyses demonstrated that the metinel nodes contained tumor-reactive lymphocytes. The metinel node derived lymphocytes proliferated in vitro upon stimulation with tumor homogenate and in nine patients we proceeded and performed adoptive immunotherapy.

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