We identified ALDH activity with significantly stronger expression of CD54 and CD55 in human articular chondrocytes. Gene expression of isotypes ALDH1A2, ALDH1A3 and ALDH2 was identified. Coexpression of ALDH activity with chondrogenic markers suggests its association with collagen II producing chondrocyte phenotype. Isotypes ALDH1A2 and ALDH1A3 can be associated with the ALDH activity in these cells.
The management of advanced ovarian cancer is challenging due to the high frequency of recurrence, often associated with the development of resistance to platinum-based chemotherapy. Molecular analyses revealed the complexity of ovarian cancer with particular emphasis on the immune system, which may contribute to disease progression and response to treatment. Cytokines and chemokines mediate the cross-talk between cancer and immune cells, and therefore, present as potential biomarkers, reflecting the tumor microenvironment. A panel of circulating C-C motif chemokine ligand (CCL) and C-X-C motif chemokine ligand (CXCL) chemokines were examined in the serum of 40 high-grade patients with ovarian cancer prior to primary surgery. The level of immune infiltration in tumors was also analyzed. The preoperative levels of chemokines differ between patients. Elevated levels of circulating CXCL4 + CCL20 + CXCL1 combination can discriminate patients with shorter recurrence-free survival and overall survival. The presence of tumor-infiltrating T lymphocytes was detected in half of the patients. The mRNA expression analysis suggests the presence of antitumoral and immunosuppressive elements in the tumor microenvironment. The combination of circulating CXCL9 + CXCL10 can distinguish immune-infiltrated tumors that will lead to shorter recurrence-free survival. The results suggest that preoperative profiling of circulating chemokines in patients with ovarian cancer may provide valuable information regarding tumor recurrence and immune infiltration. The findings demonstrate that combinations have better prognostic utility than single chemokines, and may serve as patient stratification tools.
Background/Aims: Chemotherapy resistance of malignancies is a universal phenomenon which unfavorably affects therapeutic results. Genetic adaptations as well as epigenetic factors can play an important role in the development of multidrug resistance. Cytotoxic drug content in plasma of cancer patients is known to variate up to one hundred-fold regardless of the same dose injected per m 2 body surface. The relationship between plasma concentrations, tissue uptake, and chemotherapy response is not completely understood. The main objective of this study was to investigate how the identical dose of Doxorubicin (Dox) can result in a different therapeutic response pattern depending on tumor size. Study Design: The study was performed on ascitic EL4 lymphoma in an exponential growth phase focusing on the rapidly changing tumor susceptibility to the Dox treatment. Well distinguishable tumor response patterns (curability, remission-relapse, resistance) were selected to unveil Dox intratumoral uptake and drug tissue persistence. Intratumoral Dox content within peritoneal cavity (PerC) in conjunction with systemic toxicity and plasma pharmacokinetics, were monitored at several time points following Dox injection in tumor bearing mice (TBM) with differing patterns of response. Results: Following intraperitoneal (i.p.) transplantation of 5x10 4 EL4 lymphoma cells rapid exponential proliferation with ascites volume and animal mass increase resulted in median survival of 14.5 days. The increase in tumor cell mass in PerC between day 3 and day 9 was 112.5-fold (0.2±0.03 mg vs 22.5±0.31 mg respectively). However, tumors at this time interval (day 3 to day 9 post-transplantation) were relatively small and constituted less than 0.05% of animal weight. An identical dose of Dox (15 mg/kg) injected intravenously (i.v.) on Day 3 lead to a cure whereas a TBM injected on day 9 exhibited resistance with a median survival time no different from the untreated TBM control. Injection of Dox resulted in noticeable differences of cellular uptake in PerC between all three groups of TBM ("cure", relapse", "resistance"). Larger tumors were consistently taking up less Dox 60 min after the 15 mg/kg i.v. bolus injection. Higher initial uptake resulted also in longer retention of drug in PerC cells. The area under the concentration curve in PerC cells AUC0-10d was 8.2+0.57 µg/g x h, 4.6+0.27 µg/g x h and 1.6+0.02 µg/g x h in "cure", "relapse" and "resistance" TBM respectively (p<0.05 "relapse" vs "cure" and p<0.001 "resistance" vs "cure"). No differences in plasma Dox pharmacokinetics or systemic hematological effects were observed in TBM following a single i.v. Dox push. Hematologic nadir was tested on day 2 and subsequent hematologic recovery was evaluated on day 10 following Dox administration. Hematologic recovery on day 10 coincided with complete drug efflux from PerC and rising tumor cell numbers in PerC of "relapse" TBM. Myelosuppression and hematological recovery patterns were identical in all surviving animal groups regardless of the tumor si...
Background. Cancer recurrence after adjuvant chemotherapy with long periods of remission is common. After cessation of the therapy, the dormant cells may repopulate, but the signals that control the tumor to exit dormancy are not completely understood. We hypothesized that tissue bound cytotoxic drug indwelling in a body for years might somehow contribute to dormancy or recurrence of a tumor. The purpose of this study was to design a model demonstrating that viable cells implanted in mice can repopulate or be suppressed, depending on the cytotoxic preload conditions.Methods. A two-step dormancy/recurrence (TSDR) murine model was designed, which mimics the extrusion of taken up drug from tumor cells. The viable cells preloaded with drug were implanted into mice. The survival rates of these mice were then used as criteria to demonstrate the relationship between resumed growth and drug cellular efflux/viability. The drug internalization patterns following their exposure to doxorubicin (dox) or degraded dox (dox-dgr) were investigated by exploring flow cytometry, spectral analysis, high performance liquid chromatography and confocal microscopy. Antiproliferative and myelotoxic capacity was evaluated by hematological nadir induced by the iv injected drug. Results. The viable SL2 lymphoma cells exposed to 10 µg/ml of dox for 30 min and injected into syngeneic DBA/2 mice were made unable to recure. Exposure of cells to lower dox concentrations (0.01 – 1.0 µg/ml) resulted in tumor recurrence, similar to that which was observed during implantation of an untreated tumor. Dox-dgr kept at 37 °C for 365 days lost its tumoricidal and antiproliferative capacity and displayed a loss of selectivity of nuclear fluorescence.Conclusions. Our TSDR model is a rapid convenient tool to study in vivo behavior of cells preloaded with cytotoxic drug. This approach focuses on mechanisms of tumor cells exiting dormancy, in relation to cytotoxic drug efflux. Multiple modifications of our TSDR model are possible, including nude mice models. As an example, we used one-year body temperature exposed dox to demonstrate its inability to retain sufficient cytotoxic capacity.
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