UROKINASE PLASMINOGEN-ACTIVATOR RECEPTOR (UPA-R) - ONE POTENTIAL CHARACTERISTIC OF METASTATIC PHENOTYPES IN MINIMAL RESIDUAL TUMOR DISEASE

Evidence of dynamic development of cytokeratin (CK) 18-positive dissem inated tumor cells in bone marrow of curatively resected cancer patien ts has implicated a subclinical minimal residual disease as a biologic ally relevant component in solid cancer, However, differentiation betw een irrelevant shed cells and those cells potentially capable of causi ng later recurrence has not yet been made, In parallel, accumulating d ata show functional association of the urokinase plasminogen activator (uPA) system and the membranous uPA receptor (uPA-R) with the capacit y of a tumor cell for invasion and metastasis. The present study was d esigned to find descriptive evidence in vivo concerning whether uPA-R could be one potential characteristic for metastatically relevant phen otypes of disseminated tumor cells. An immunocytochemical double stain ing for uPA-R and CK18 (immunogold/alkaline phosphatase anti-alkaline phosphatase) was performed on perioperative and follow-up bone marrow aspirations of 78 curatively resected gastric cancer patients, if posi tive tumor cell status had been shown previously with the single alkal ine phosphatase anti-alkaline phosphatase method, Bone marrow cells (1 0(6)) were examined in each assay, Postoperative qualitative and quant itative development of uPA-R-expressing disseminated tumor cells was f ollowed in relation to uPA-R-negative cells and correlated with later clinical relapse. Double staining could be performed perioperatively o r in follow-up, or both, in 58 of 78 patients, Expression of uPA-R on perioperatively disseminated tumor cells significantly correlated with later quantitative in creases of tumor cells (P = 0.0009), Overall me dian tumor cell numbers with uPA-R expression significantly increased during follow-up from a median value of 5.5 to 10.0 in 10(6) cells (P = 0.008), and the mean relative percentage of uPA-R-positive, compared with uPA-R negative, disseminated tumor cells also increased, from 47 .9% at surgery to 68.6% in follow-up (P < 0.001), This was mainly due to patients with later tumor relapse (increase from 63.9 to 80.7%, P = 0.001), Patients without relapse showed slight increases at lower per centage levels (5.7% at surgery, 7.4% in follow-up), Differences for r elapsing patients were significant (surgery, P = 0.006; follow-up, P < 0.001). Our results suggest from an in vivo model that uPA-R may be o ne antigen that enables identification and follow-up observations of m etastatically relevant phenotypes of disseminated tumor cells, differe ntiating their individual potential for causing relapse.