Abstract
BackgroundCancer cells are known to secrete the stress molecules MICA and MICB that activate cytotoxicity by lymphocytes and NK cells through their NKG2D receptor as a mechanism of immunological defense. This work was undertaken to evaluate if cancer cells can also express this receptor as a possible mechanisms of depletion of MIC molecules and thus interfere with their immune recognition.MethodsMyelomonocytic leukemic (TPH-1 and U-937) and cervical cancer (CALO and INBL) cell lines were evaluated by Western Blot, ELISA, flow cytometry and immunocytochemistry to evaluate their capacity to express and secrete MICA and MICB and to be induced to proliferate by these molecules as well as to express their receptor NKG2D. Statistical analysis was performed by two-way ANOVA for time course analysis and Student's t-test for comparison between groups. Values were considered significantly different if p < 0.05.ResultsTHP-1 and U-937 produce and secrete the stress MICA and MICB as shown by Western Blot of lysed cells and by ELISA of their conditioned media. By Western Blot and flow cytometry we found that these cells also express the receptor NKG2D. When THP-1 and U-937 were cultured with recombinant MICA and MICB they exhibited a dose dependent induction for their proliferation. CALO and INBL also produce MICA and MICB and were induced to proliferate by these stress molecules. By Western Blot, flow cytometry and immunocytochemistry we also found that these cells express NKG2D.ConclusionsOur novel results that tumor cells can simultaneously secrete MIC molecules and express their receptor, and to be induced for proliferation by these stress molecules, and that tumor epithelial cells can also express the NKG2D receptor that was thought to be exclusive of NK and cytotoxic lymphocytes is discussed as a possible mechanism of immunological escape and of tumor growth induction.
Highlights
Cancer cells are known to secrete the stress molecules MICA and MICB that activate cytotoxicity by lymphocytes and NK cells through their NKG2D receptor as a mechanism of immunological defense
The leukemic myelomonocytic U-937 and THP-1 cell lines produce and secrete MICA and MICB In order to evaluate if the leukemic myelomonocytic U-937 and TPH-1 cell lines produce MICA and MICB, we performed a western blot analysis using specific antibodies against MICA and MICB and found that both proteins were expressed in both cell lines (Figure 1A)
Using ELISA, we determined that MICA and MICB were secreted into the conditioned media (CM) from the first day of culture (Figure 1B)
Summary
Cancer cells are known to secrete the stress molecules MICA and MICB that activate cytotoxicity by lymphocytes and NK cells through their NKG2D receptor as a mechanism of immunological defense. The ligands for NKG2D include the human class I-like molecules MICA and MICB [5], which are stress-induced molecules expressed by tumors of epithelial origin [6,7] and, leukemias [8], as well as by virus-infected cells [9,10]. This work was undertaken to determine if two human leukemic myelomonocytic cell lines, THP-1 and U-937, produce MICA and MICB and express NKG2D, and if these stress molecules induce cell proliferation. In order to determine if these properties are shared by other tumors, we analyzed the CALO and INBL human epithelial cervical cancer cell lines
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