| 1. |
- Cerezo-Magaña, M., et al.
(författare)
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The pleiotropic role of proteoglycans in extracellular vesicle mediated communication in the tumor microenvironment
- 2020
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Ingår i: Seminars in Cancer Biology. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 1044-579X .- 1096-3650. ; 62, s. 99-107
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Forskningsöversikt (refereegranskat)abstract
- Compartmental exchange between cells through extracellular vesicles (EVs), including exosomes and microvesicles, has emerged as a central mechanism that coordinates the complex communication between malignant and stromal cells during tumor initiation and evolution. Some of the most critical processes of EV-mediated communication, including EV biogenesis and EV uptake, can be mediated by heparan sulfate proteoglycans (HSPGs) that reside on the surface of producer and recipient cells as well as on EVs. With interestingly similar, HSPG-dependent, pathways as the ones exploited by some viruses, EVs may, in an evolutionary perspective, be viewed as endogenous counterparts of viral particles. Cancer cell-derived EVs exert their protumorigenic effects by direct interactions of biologically active surface molecules, by transfer of proteins and nucleic acids into recipient cells or by transfer of metabolites that can be utilized as an energy source by the recipient cell. Here, we discuss the pleiotropic role of the HSPG family in these different contexts of EV communication with a specific focus on tumor development. We propose EV-associated PGs as dynamic reservoirs and chaperones of signaling molecules with potential implications in ligand exchange between EVs and tumor target cells. The protumorigenic consequences of EV mediated communication through HSPG should motivate the development of therapeutic approaches targeting EV-HSPG interactions as a novel strategy in cancer treatment.
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| 2. |
- Chandran, Vineesh Indira, et al.
(författare)
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Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656
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Tidskriftsartikel (refereegranskat)abstract
- The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
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| 3. |
- Feldt, Maria, et al.
(författare)
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The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression : a window-of-opportunity breast cancer trial
- 2020
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Ingår i: Cancer & Metabolism. - : BMC. - 2049-3002. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.Methods: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level.Results: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P = 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance.Conclusions: This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation.
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