Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells.

Natural killer (NK) cells are cytotoxic lymphocytes that play an important role in tumor immunosurveillance, preferentially eliminating targets with low or absent expression of MHC class I and stress-induced expression of ligands for activating NK receptors. Platelets promote metastasis by protecting disseminating tumor cells from NK cell immunosurveillance, but the underlying mechanisms are not well understood. In this study, we show that tumor cells rapidly get coated in the presence of platelets in vitro, and circulating tumor cells of cancer patients display coexpression of platelet markers. Flow cytometry, immunofluorescent staining, confocal microscopy, and analyses on an ultrastructural level using immunoelectron microscopy revealed that such coating may cause transfer of MHC class I onto the tumor cell surface resulting in high-level expression of platelet-derived normal MHC class I. The resulting "phenotype of false pretenses" disrupts recognition of tumor cell missing self, thereby impairing cytotoxicity and IFN-γ production by NK cells. Thus, our data indicate that platelets, by conferring an unsuspicious "pseudonormal" phenotype, may enable a molecular mimicry that allows metastasizing tumor cells to downregulate MHC class I, to escape T-cell-mediated immunity without inducing susceptibility to NK cell reactivity.

[Severe hemorrhage in a patient with metastatic colorectal cancer - case 8/2012]. / Schwere Blutungen bei einer Patientin mit metastasierendem Kolonkarzinom - Fall 8/2012.

HISTORY AND ADMISSION FINDINGS: We report on a 65-year-old female patient with a recent diagnosis of adenocarcinoma of the sigmoid colon and massive hematochezia in the context of a general bleeding disorder. INVESTIGATIONS: Disseminated malignant disease with hepatic metastases as well as bone marrow involvement was demonstrated. Moreover, circulating tumor cells were demonstrated by flow cytometry. The patient had right lower quadrant abdominal pain due to a spontaneous psoas intramuscular hematoma. DIAGNOSIS, TREATMENT AND COURSE: At the time of admission to our hospital, the patient displayed microangiopathic hemolytic anemia and secondary hyperfibrinolysis with a pronounced bleeding tendency. Moreover, there was an acute renal failure which improved with fluid resuscitation. With immediate chemotherapy consisting of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX regimen) and cetuximab initiated with the second course, plasmatic coagulation could be stabilized. Consequently, treatment with tranexamic acid, fibrinogen, fresh frozen plasma as well as red blood cell and platelet infusions could be stopped. Continuation of chemotherapy was possible on an outpatient basis and the further course was associated with a good quality of life until her near end. The patient died at home 7 months after initial diagnosis of her colon cancer due to progressive disease with CNS metastases. CONCLUSIONS: Disseminated intravascular coagulation with microangiopathic hemolysis and secondary hyperfibrinolysis is a rare albeit possible event in disseminated colorectal cancer, especially when the bone marrow is involved. Treatment of the underlying cause is the most important therapeutic measure.

The mesenchymal stem cell antigen MSCA-1 is identical to tissue non-specific alkaline phosphatase.

We have recently identified 2 distinct CD271(bright)MSCA-1(dim)CD56(+) and CD271(bright)MSCA-1(bright)CD56(-) MSC subsets in primary femur-derived bone marrow (BM), which differ in their expression pattern and morphology as well as in their clonogenic and differentiation capacity. Here, we show that MSCA-1 is identical to tissue non-specific alkaline phosphatase (TNAP), an ectoenzyme known to be expressed at high levels in liver, bone, and kidney as well as in embryonic stem (ES) cells. SDS-PAGE of WERI-RB-1 cell lysate and supernatant from phosphatidylinositol-specific phospholipase C (PI-PLC)-treated WERI-RB-1 cells resulted in the appearance of a prominent 68-kDa band. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDITOF MS) sequence analysis revealed TNAP-specific peptides. Screening of the MSCA-1-specific antibody W8B2 on HEK-293 cells transfected with the full-length coding sequence of TNAP showed specific reactivity with transfected but not with parent cell line. In addition, TNAP-specific mRNA expression was selectively detected in the transfectant line. In agreement with these findings, enzymatic activity of TNAP was exclusively detected in sorted MSCA-1(+) BM cells but not in the MSCA-1(-) negative fraction. Surface marker analysis revealed coexpression of the embryonic marker SSEA-3 but not SSEA-4, TRA-1-60, and TRA-1-81. In endometrium, TNAP is expressed at intermediate levels on CD146(+) cells and at high levels in the luminal space of glandular epithelia. Our results demonstrate that TNAP is a selective marker for the prospective isolation of BM-derived MSC and MSC-like cells in endometrium.