The prognostic significance of transketolase-like protein 1 in gastrointestinal malignancies

Background: Cancer is the second most common cause of death nowadays. Gastrointestinal malignancies account for over 20% of cancer deaths globally. The prognosis in colorectal cancer has improved over the years while that of pancreatic and stomach has remained poor for the past decade. Biochemical tumor markers help in subtyping cancers to aim in choosing the best possible treatment for each individual. They are also helpful in follow-up and in determining prognosis. Cancer cells have metabolic features that differ from non-cancerous cells. One of these is the ability to use glycolysis as an energy source. Transketolase-like protein 1 (TKTL1) is a protein that catalyses cancer cells’ glucose production via the pentose phosphate pathway. This thesis consists of four studies that aimed to investigate the potential of TKTL1 as a prognostic marker in gastrointestinal cancers. Materials and methods: Study I included 840 colorectal patients treated in 1989-2000. The second study comprised 111 patients with colorectal cancer and liver metastases thereof. These patients were operated on in 1988-2007. Formalin-fixed samples were obtained from the primary tumor and liver metastases in 60 patients, the primary tumor only in 21 patients and liver metastases only in 30 patients. Study III included 313 patients with gastric cancer surgically treated in 2000-2009. Study IV on pancreatic ductal adenocarcinoma (PDAC) comprised 168 patients who were treated surgically in 2001-2011. All patients were treated at the Department of Surgery at Helsinki University Hospital. Clinicopathological data was gathered from patient records and causes of death from Statistics Finland. For all patients, tissue micro array (TMA) series were constructed including 3-6 tumor spots per patient. For study IV whole tissue samples were used in addition to TMA blocks. All tissue samples were stained for TKTL1 using immunohistochemistry. In study III also Glucose transporter 1 (GLUT1) staining was done. Results: TKTL1 immunostaining occurs mostly in cytoplasm although nucleus staining can also be seen. TKTL1 positivity is typical for cancer cells, but weak expression can occur in normal cells. In study I on colorectal cancer, TKTL1 associated with Dukes stage B through D, with left-sided disease, and with adenocarcinoma. Patients with high tissue expression of TKTL1 had poor prognosis but TKTL1 was not an independent prognostic factor. In study II, in the subgroup of patients with synchronous liver metastasis, the prognosis was poor in those with a high expression of TKTL1 in primary tumor tissue. In gastric cancer (study III), positive TKTL1 immunostaining associated with positive immunostaining of GLUT1, higher age, male gender, and advanced stage disease (stage II-IV and pT2-4). GLUT1 associated with intestinal type of cancer. TKTL1 served as a marker of poor prognosis in gastric cancer, but not independent, but GLUT1 did not have any prognostic value. Contradictory to previous findings in other cancer types, study IV showed that high expression of TKTL1 in PDAC was a marker of better prognosis in patients over 65 years old and those with distant metastasis, perivascular invasion and stage IV disease, but had no prognostic value in general. Conclusions: TKTL1 was a marker of poor prognosis among patients with colorectal cancer and also among those with synchronous liver metastases and those with intestinal or diffuse gastric cancer. TKTL1 cannot be used as a general prognostic marker in pancreatic ductal adenocarcinoma.