Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy

<p>Abstract</p> <p>Background</p> <p>Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).</p> <p>Methods</p> <p>We isolated a breast cancer cell population (CD44⁺CD24^-cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44⁺CD24^-phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.</p> <p>Results</p> <p>Knockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.</p> <p>Conclusions</p> <p>Knockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.</p

Is Evolution of Blind Mole Rats Determined by Climate Oscillations?

The concept of climate variability facilitating adaptive radiation supported by the ‘‘Court Jester’’ hypothesis is disputed by the ‘‘Red Queen’’ one, but the prevalence of one or the other might be scale-dependent. We report on a detailed, comprehensive phylo-geographic study on the ,4 kb mtDNA sequence in underground blind mole rats of the family Spalacidae (or subfamily Spalacinae) from the East Mediterranean steppes. Our study aimed at testing the presence of periodicities in branching patterns on a constructed phylogenetic tree and at searching for congruence between branching events, tectonic history and paleoclimates. In contrast to the strong support for the majority of the branching events on the tree, the absence of support in a few instances indicates that network-like evolution could exist in spalacids. In our tree, robust support was given, in concordance with paleontological data, for the separation of spalacids from muroid rodents during the first half of the Miocene when open, grass-dominated habitats were established. Marine barriers formed between Anatolia and the Balkans could have facilitated the separation of the lineage ‘‘Spalax’’ from the lineage ‘‘Nannospalax’’ and of the clade ‘‘leucodon’’ from the clade ‘‘xanthodon’’. The separation of the clade ‘‘ehrenbergi’’ occurred during the late stages of the tectonically induced uplift of the Anatolian high plateaus and mountains, whereas the separation of the clade ‘‘vasvarii’’ took place when the rapidly uplifting Taurus mountain range prevented the Mediterranean rainfalls from reaching the Central Anatolian Plateau. The separation of Spalax antiquus and S. graecus occurred when the southeastern Carpathians were uplifted. Despite the role played by tectonic events, branching events that show periodicity corresponding to 400-kyr and 100-kyr eccentricity bands illuminate the important role of orbital fluctuations on adaptive radiation in spalacids. At the given scale, our results supports the ‘‘Court Jester’’ hypothesis over the ‘‘Red Queen’’ one

Subductions, obduction and collision in the Lesser Caucasus (Armenia, Azerbaijan, Georgia), new insights

In the Lesser Caucasus three main domains are distinguished from SW to NE: (1) the autochthonous South Armenian Block (SAB), a Gondwana-derived terrane; (2) the ophiolitic Sevan–Akera suture zone; and (3) the Eurasian plate. Based on our field work, new stratigraphical, petrological, geochemical and geochronological data combined with previous data we present new insights on the subduction, obduction and collision processes recorded in the Lesser Caucasus. Two subductions are clearly identified, one related to the Neotethys subduction beneath the Eurasian margin and one intra-oceanic (SSZ) responsible for the opening of a back-arc basin which corresponds to the ophiolites of the Lesser Caucasus. The obduction occurred during the Late Coniacian to Santonian and is responsible for the widespread ophiolitic nappe outcrop in front of the suture zone. Following the subduction of oceanic lithosphere remnants under Eurasia, the collision of the SAB with Eurasia started during the Paleocene, producing 1) folding of ophiolites, arc and Upper Cretaceous formations (Transcaucasus massif to Karabakh); 2) thrusting toward SW; and 3) a foreland basin in front of the belt. Upper–Middle Eocene series unconformably cover the three domains. From Eocene to Miocene as a result of the Arabian plate collision with the SAB to the South, southward propagation of shortening featured by folding and thrusting occurred all along the belt. These deformations are sealed by a thick sequence of unconformable Miocene to Quaternary clastic and volcanic rocks of debated origin

A Preliminary Framework for Magmatism in Modern Continental Back‐Arc Basins and Its Application to the Triassic‐Jurassic Tectonic Evolution of the Caucasus

Abstract Extension within a continental back‐arc basin initiates within continental rather than oceanic lithosphere, and the geochemical characteristics of magmatic rocks within continental back‐arcs are poorly understood relative to their intraoceanic counterparts. Here, we compile published geochemical data from five exemplar modern continental back‐arc basins—the Okinawa Trough, Bransfield Strait, Tyrrhenian Sea, Patagonia plateau, and Aegean Sea/Western Anatolia—to establish a geochemical framework for continental back‐arc magmatism. This analysis shows that continental back‐arcs yield geochemical signatures more similar to arc magmatism than intraoceanic back‐arcs do. We apply this framework to published data for Triassic‐Jurassic magmatic rocks from the Caucasus arc system, which includes a relict continental back‐arc, the Caucasus Basin, that opened during the Jurassic and for which the causal mechanism of formation remains debated. Our analysis of 40Ar/39Ar and U‐Pb ages indicates Permian‐Triassic arc magmatism from ∼260 to 220 Ma due to subduction beneath the Greater Caucasus and Scythian Platform. Late Triassic (∼220–210 Ma) collision of the Iranian block with Laurasia likely induced trench retreat in the Caucasus region and led to migration of the Caucasus arc and opening of the Caucasus Basin. This activity was followed by Jurassic arc magmatism in the Lesser Caucasus from ∼180 to 140 Ma and back‐arc spreading in the Caucasus Basin from ∼180 to 160 Ma. Trace element and Sr‐Nd isotopic data for magmatic rocks indicate that Caucasus Basin magmatism is comparable to modern continental back‐arcs and that the source to the Lesser Caucasus arc became more enriched at ∼160 Ma, likely from the cessation of back‐arc spreading