bluuebunny/crossref_metadata_2025 huggingface dataset:
Palaeobiogeography of Cretaceous bony fishes (Actinistia, Dipnoi and Actinopterygii)
Authors: Cavin Lionel
Published: June 2008

Dispersal and vicariant patterns have been used as opposite concepts to explain biogeographical histories of organisms. Vicariance has been preferred to dispersal: the former is said to be falsifiable while the latter is regarded as a contingent hypothesis. If included in a temporal framework, however, a sister-group relationship between two taxa could be more parsimoniously explained by a dispersal event if both taxa are not contemporaneous in time. Published phylogenies of various clades of bony fishes are compared with evolution of the palaeogeographical framework during the Cretaceous, and possible causes involved in the observed patterns, such as vicariant events, dispersal events or radiations are suggested. Most Cretaceous patterns concerns east–west events (vicariance and dispersal) rather than north–south events. This is probably because the separation of Laurasia and Gondwana is already underway in the Late Jurassic and affected Cretaceous faunas only weakly. Late Cretaceous dispersal patterns constitute a more common phenomenon than previously expected. It is suggested that the entire autoecology of the fishes is a more significant parameter affecting dispersal ability than only their allegedly capacity to tolerate salt waters.
Fossil Mooneyes (Teleostei: Hiodontiformes, Hiodontidae) from the Eocene of western North America, with a reassessment of their taxonomy
Authors: Hilton Eric J. , Grande Lance
Published: June 2008

The skeletal anatomy of fossil hiodontids from western North America is examined based on newly-prepared specimens, including several specimens that were prepared using the acid transfer method and some using the ‘lost fossil’ technique. This study resulted in many new interpretations and clarifications, such as the presence of a curved tubular nasal bone and a posterodorsal spine on the opercle of ‘†
Eohiodon
’, as found in extant
Hiodon
. We also further describe the variation of the caudal skeleton that has been known in both fossil and extant
Hiodon
. For instance, the neural spine of preural one is most often fully developed (as it is in a minority of extant
Hiodon
specimens), although in some specimens it is rudimentary, as it is in most specimens of living taxa. We review the characters that have been used in recent analyses of relationships of osteoglossomorph fishes. After correcting the descriptions of the fossil taxa, we could find no valid synapomorphies to separate the genus †
Eohiodon
from the genus
Hiodon
. Therefore, we conclude that †
Eohiodon
should be regarded as a synonym of
Hiodon
.
Osteoglossomorphs of the marine Lower Eocene of Denmark – with remarks on other Eocene taxa and their importance for palaeobiogeography
Authors: Bonde Niels
Published: June 2008

The geological, faunal and palaeoecological conditions of the marine deposits from lowermost Eocene in North Jutland are briefly reviewed as background for the descriptions of six species of osteoglossiform fishes from the Stolle Klint Clay and the overlying Mo-clay (Ølst and Fur Formations respectively). Four of these primitive teleosteans are referred to new genera and species (one based on an almost complete skeleton, three others on skull material, one very incomplete), and the two most fragmentary specimens are referred to
Brychaetus
sp. and an indeterminate osteoglossiform. The phylogenetic relationships of these fossils are evaluated in the framework of two different models of osteoglossomorph phylogeny provided earlier by Taverne and Hilton. Despite differences in both data bases, methodologies and results given by the two models (the former based on
c
. 300 characters in an intuitive, qualitative phylogenetic parsimony analysis, the latter on 72 characters in a critical, rigorous, quantitative cladistic analysis) the phylogenetic positions of four of the fossil species are very similar in the two models concerning the relations to the recent forms. The other two species, rather fragmentary, but similar in many ways to the Eocene phareodonts (paraphyletic group), end up very differently in relation to extant forms in the two models. The phylogenetic systematics of all the marine, fossil osteoglossiforms (including
Brychaetus, Opsithrissops
and Monte Bolca forms) is evaluated as background for interpretation of their (palaeo-)biogeographic significance as marine members of a group, Osteoglossomorpha (of which the recent forms are prime examples of ‘primary division freshwater fishes', and of which the extant osteoglossiforms have a classical ‘Gondwana distribution’. There are 9 marine, Eocene taxa (plus an otolith from the Maastrichtian of USA) and none of the 9 appear more closely-related to any other marine form in either model: they might constitute 9 separate migrations from freshwater into the sea. The phylogenetic results strongly suggest instead, that the extant osteoglossiforms have independently entered freshwater from the sea on two, perhaps even three occasions. This may have happened as late as the Eocene, and phareodonts could be yet another independent invasion of freshwater in the Late Cretaceous. The mormyriforms most likely had an independent invasion into freshwater (in one model even with notopterids as a separate migration from the sea by Mid or Early Cretaceous). Because all the closest outgroups of the Osteoglossomorpha are marine, the group obviously originated in the sea, probably by the Late Jurassic, and it is not impossible that Hiodontiforms in NE Asia and North America underwent another independent freshwater invasion very early in the Cretaceous. What then is wanting? The expected Cretaceous, marine osteoglossomorphs are not found (but note the above otolith).
New information on the cranial anatomy of the eel genus
Echelus
Rafinesque, 1810 (Ophichthidae: Anguilliformes) from the Early Eocene
Authors: Young Sally V. T. , Williams R. J.
Published: June 2008

Two neurocrania of the eel genus
Echelus
Rafinesque, 1810 were collected from the London Clay Formation, Eocene, from Aveley, Essex. They are identified herein as
E. branchialis
Woodward, 1901. One specimen retains an incomplete premaxillary ethmo vomerine plate, normally lost in fossil specimens, and provides further anatomical information and taxonomic characters for this species.

The geographical range of the species is extended and localities of fossil species of
Echelus
and other fossil taxa believed by various authors to be closely-related to
Echelus
species are depicted on a map of the distribution of continental crust in the northern hemisphere during Oligocene times. The distribution of such eel taxa is consistent with the supposed extent of the Eocene sea within Europe. It would appear that modern species of
Echelus
now occupy areas that are more cosmopolitan than the fossil species. During the break-up of Pangaea and the subsequent expansion of the Atlantic and Indo-Pacific Oceans species of
Echelus
have ventured beyond their original provenance of continental sea and now occupy habitats along margins of the eastern Atlantic and of the western and eastern Indo-Pacific Oceans.
Fossil Cypriniformes from China and its adjacent areas and their palaeobiogeographical implications
Authors: Chang Mee-mann , Chen Gengjiao
Published: June 2008

Fossil cypriniforms are abundantly represented in China and its adjacent areas, with the described taxa approximating to a total of 80 genera and 100 species and subspecies. They are known mainly from the Eocene, Miocene and Pliocene deposits. The Oligocene and Quaternary materials are relatively rare. These fossil cypriniforms represent three of the five Recent families: the Catostomidae, Cobitidae and Cyprinidae. Comparison of the Eocene catostomids from mainland East Asia with those from western North America points to an obvious transpacific distributional pattern, whereas there is only one species in Asia and more than 70 species in North America at present. Fossil cobitids are comparatively rare. Cyprinids are the most diverse and widespread group among the three families. The Miocene and Pliocene taxa shared by east mainland Asia and the Japanese Islands indicate that the fishes from these areas must have belonged to the same ichthyofauna during the Neogene. At the same time, some of them are quite similar to those from Europe, which is indicative of a closer connection between the two areas than previously thought.
Can the comparative study of the morphology and histology of the scales of
Latimeria menadoensis
and
L. chalumnae
(Sarcopterygii: Actinistia, Coelacanthidae) bring new insight on the taxonomy and the biogeography of recent coelacanthids?
Authors: Meunier François J. , Erdmann Mark V. , Fermon Yves , Caldwell Roy L.
Published: June 2008

SEM (Scanning electron microscopy) and photonic microscopy (ground sections) studies confirm that the scales of the coelacanth
Latimeria menadoensis
have strong morphological and histological similarities with the scales of
L. chalumnae
. They are both elasmoid scales, the external layer of which is made of radial ridges that are overlaid, on the posterior field, by odontodes. The odontodes of
L. menadoensis
are made of the typical mineralized tissues described for teeth of the coelacanth and their width is similar to that of
L. chalumnae
odontodes. Globular corpuscles are found in the isopedine contact with the external layer. Their mineralization seems to be inotropic as in the Mandl's corpuscles of teleost elasmoid scales. Scale organisation in
L. menadoensis
does not show any characteristics that may support significantly, in the absence of additional evidence, two different species in the extant coelacanths.
The first Triassic lungfish from South America (Santa Maria Formation, Paraná Basin) and its bearing on geological correlations within Pangaea
Authors: Richter M. , Toledo C. E. V.
Published: June 2008

The Triassic fish faunas of the Southern Hemisphere are only known from a few sedimentary basins and the most productive sites are those from the Karoo Supergroup, in South Africa and the Sydney Basin of Australia. A single lungfish tooth plate ascribed to
Ptychoceratodus
cf.
philippsi
was recovered from Late Triassic (Carnian) red beds of southern Brazil and is described herein. This find extends to South America the palaeogeographic distribution of the genus, which occurs in the Early Triassic of Australia and South Africa and the Middle/Late Triassic of Europe and Late Triassic of Madagascar and India. The presence of this dipnoan solely in the uppermost part of the Santa Maria Formation suggests that the migration of
Ptychoceratodus
towards the Paraná Basin began not before the late Induan/early Olenekian (late Early Triassic). At that time, more humid (monsoonal) conditions prevailed in what is now southern Brazil, compared to semi-arid/desert conditions that dominated the Late Permian and possibly the earliest Early Triassic (the latter presumably not represented in the Paraná Basin).
Diversity and biogeography patterns of Late Jurassic neoselachians (Chondrichthyes: Elasmobranchii)
Authors: Kriwet Jürgen , Klug Stefanie
Published: June 2008

The regional diversity and biogeographic patterns of Late Jurassic neoselachians at genus level in Europe were analysed based on samples and an extensive literature survey of about 40 localities ranging from the Oxfordian to Tithonian. The simple completeness metric (SCM) displays a quite good fossil record of neoselachians in the Late Jurassic with a peak in the Kimmeridgian. The origination, extinction, diversification and turnover rates were calculated for every stage and indicate that background origination occurred in the Oxfordian and Kimmeridgian with no disappearance of genera. In the Tithonian, background extinction is the main factor for neoselachian diversity decline. The decline in neoselachian diversity at the end of the Jurassic is most probably related to reduced habitats in the course of major regression events, establishment of physical barriers, and climatic changes. Faunal assemblages are quite uniform and mostly agree well with the contemporaneous palaeogeographic situation. Our analyses indicate that both vicariance and dispersal were important processes in the biogeographic pattern of Late Jurassic neoselachians.
The varasichthyid and other crossognathiform fishes, and the Break-up of Pangaea
Authors: Arratia Gloria
Published: June 2008

Crossognathiforms have been traditionally considered typical marine Cretaceous forms widely represented in the Northern Hemisphere and by a few members in Brazil. During the last 30 years they have been interpreted as Teleostei
incertae sedis
, clupeocephalans or a non-monophyletic group. New evidence indicates that the Oxfordian taxon
Chongichthys
(previously considered a Teleostei
incertae sedis
or a clupeocephalan), the Late Jurassic family Varasichthyidae (interpreted as basal teleosts), and the crossognathoids and pachyrhizodontoids form a clade here recognized as the Crossognathiformes. Varasichthyids are the sister group of a clade including
Chongichthys
(at the base) and crossognathoids+pachyrhizodontoids. The Crossognathiformes (including Varasichthyidae and
Chongichthys
) are basal teleosts placed between the Late Jurassic basal genera
Tharsis
and
Ascalabos
in one tree or between
Ascalabos
and the ichthyodectiforms in the second tree. The position of elopomorphs as the most basal extant teleosts is confirmed. A new interpretation of the phylogenetic position of the clade [
Humbertia
+[
Erichalcis
+[
Leptolepides
+
Orthogonikleithrum
]]], at the base of clupeocephalans, is suggested.

The presence of the Late Jurassic varasichthyids (e.g.
Domeykos
) in South America (Chile) and Central America (Cuba;
Luisichthys
), and
Chongichthys
(Chile), and of the Late Jurassic genera
Ascalabos
and
Tharsis
and the ichthyodectiforms (e.g.
Allothrissops
) in Europe (e.g. Germany) allows the proposal of a sister-area relationship between Chile and Cuba, which was the sister area of Germany during the Late Jurassic. The Late Jurassic connection between the Palaeopacific (Chilean region) and the Tethys Sea (southern Germany) was through the newly formed Central Atlantic Ocean (Cuban region) as a result of the break up of Pangaea and separation of North America, South America and Africa.
Hybodont sharks from the lower Cretaceous Khok Kruat Formation of Thailand, and hybodont diversity during the Early Cretaceous
Authors: Cuny G. , Suteethorn V. , Kamha S. , Buffetaut E.
Published: June 2008

Isolated teeth of five hybodont species are described from the Khok Kruat Formation (Aptian):
Hybodus aequitridentatus
nov. sp.,
Heteroptychodus steinmanni
,
Thaiodus ruchae, Khoratodus foreyi
nov. gen. et nov. sp., and
Acrorhizodus khoratensis
. A new family, Thaiodontidae is also erected for
Thaiodus
and
Khoratodus.
Two species are recognized inside the genus
Heteroptychodus, H. steinmanni
and
H. chuvalovi
nov. comb. These sharks show a wide range of diet and many of them appear to be restricted to a freshwater environment and thus are probably endemic to the Khorat Plateau. However,
Thaiodus
and
Heteroptychodus
are also found in deltaic and/or marine environments outside Thailand, but are nevertheless restricted to the Asian continent. It seems that the appearance of three different palaeobiogeographical provinces (Europe, Asia and Africa–South America) around the Tethys during the Early Cretaceous led to the highest diversity at the generic level in the history of hybodont sharks.
A new species of
Placidichthys
(Halecomorphi: Ionoscopiformes) from the Lower Cretaceous Marizal Formation, northeastern Brazil, with a review of the biogeographical distribution of the Ophiopsidae
Authors: Brito Paulo M. , Alvarado‐Ortega Jesús
Published: June 2008

A new halecomorph fish is described from the Early Cretaceous Marizal Formation of Tucano Basin. This new material is identified as a new species of
Placidichthys, P. tucanensis
sp. nov. based on the absence of an anal fin, the lower number of flank scales in the caudal region, the slender shape of the body, and body proportions.
Placidichthys tucanensis
sp. nov. increases the distribution and diversity of ophiopsids in the western part of the Tethys Sea, being distributed along the epicontinental seas of Gondwana.

Placidichthys
is considered the sister-taxon of the exclusively Cretaceous taxa
Teoichthys
+
Macrepistius
from the western Tethys. These groups show a discernible geographical distribution pattern with
Placidichthys
known only from the Southern margin of the Tethys region (South America), whilst
Teoichthys
and
Macrepistius
are known only from North America and possibly Europe.
Cancer Suppression at Old Age
Authors: Harding Charles , Pompei Francesco , Lee Ellen E. , Wilson Richard
Published: June 2008

Increased age is regularly linked with heightened cancer risk, but recent research suggests a flattening around age 80. We report that, independent of cancer site or time period, most incidence rates decrease in the more elderly and drop to or toward zero near the ceiling of human life span. For all major organ sites, male and female, we use 1979 to 2003 Surveillance, Epidemiology, and End Results registry records (8–26% of the U.S. population) to construct three sequential cross-sections at 10-year intervals, totaling 129 sets of age-specific cancer data. To compute incidence rates, we estimate older populations at risk with census counts and NIH life tables. This article provides both a minimal and a more comprehensive extension of Surveillance, Epidemiology, and End Results cancer rates to those above 85. Almost all cancers peak at age ∼80. Generally, it seems that centenarians are asymptomatic or untargeted by cancers. We suggest that the best available justification for this pattern of incidence is a link between increased senescence and decreased proliferative potential among cancers. Then, thus far, as senescence may be a carcinogen, it might also be considered an anticarcinogen in the elderly. We model rising and falling incidence rates with a β curve obtained by appending a linearly decreasing factor to the well-known Armitage-Doll multistage model of cancer. Taken at face value, the β model implies that medical, diet, or lifestyle interventions restricting carcinogenesis ought to be examined for possible effects on longevity. [Cancer Res 2008;68(11):4465–78]
The Roles of Human Sucrose Nonfermenting Protein 2 Homologue in the Tumor-Promoting Functions of Rsf-1
Authors: Sheu Jim Jinn-Chyuan , Choi Jung Hye , Yildiz Isil , Tsai Fuu-Jen , Shaul Yosef , Wang Tian-Li , Shih Ie-Ming
Published: June 2008

Rsf-1 interacts with human sucrose nonfermenting protein 2 homologue (hSNF2H) to form a chromatin remodeling complex that participates in several biological processes. We have previously shown that Rsf-1 gene amplification was associated with the most aggressive type of ovarian cancer and cancer cells with Rsf-1 overexpression depended on Rsf-1 to survive. In this report, we determine if formation of the Rsf-1/hSNF2H complex could be one of the mechanisms contributing to tumor cell survival and growth in ovarian carcinomas. Based on immunohistochemistry, we found that Rsf-1 and hSNF2H were co-upregulated in ovarian cancer tissues. Ectopic expression of Rsf-1 in SKOV3 ovarian cancer cells with undetectable endogenous Rsf-1 expression enhanced hSNF2H protein levels and promoted SKOV3 tumor growth in a mouse xenograft model. Our studies also indicated that induction of Rsf-1 expression affected the molecular partnership of hSNF2H and translocated hSNF2H into nuclei where it colocalized with Rsf-1. Furthermore, analysis of Rsf-1 deletion mutants showed that the Rsf-D4 fragment contained the hSNF2H binding site based on coimmunoprecipitation and in vitro competition assays. As compared with other truncated mutants, expression of Rsf-D4 resulted in remarkable growth inhibition in ovarian cancer cells with Rsf-1 gene amplification and overexpression, but not in those without detectable Rsf-1 expression. The above findings suggest that interaction between Rsf-1 and hSNF2H may define a survival signal in those tumors overexpressing Rsf-1. [Cancer Res 2008;68(11):4050–7]
Unraveling the Mystery of Erythropoietin-Stimulating Agents in Cancer Promotion
Authors: May Kelly A. , Khuri Fadlo R.
Published: June 2008

Erythropoietin-stimulating agents (ESA) are approved for use in treating chemotherapy-induced anemia in patients with nonmyeloid malignancies. However, recent clinical trials have shown evidence of inferior overall survival and/or locoregional control of tumors in patients receiving ESAs. Given these concerning data, current studies are focused on elucidating the biological mechanisms by which ESAs may contribute to cancer promotion. Evidence suggests that ESAs activate several signaling pathways that are important in altering tumor behavior and response to treatment. Although further research is needed to more precisely elucidate these mechanisms, caution should be exercised in the use of ESAs beyond their approved indication in cancer patients. [Cancer Res 2008;68(11):4013–7]
Inhibition of STAT3Tyr705 Phosphorylation by Smad4 Suppresses Transforming Growth Factor β–Mediated Invasion and Metastasis in Pancreatic Cancer Cells
Authors: Zhao Shujie , Venkatasubbarao Kolaparthi , Lazor Jillian W. , Sperry Jane , Jin Changqing , Cao Lin , Freeman James W.
Published: June 2008

The role of Smad4 in transforming growth factor β (TGFβ)–mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in expression of Smad4. Cells expressing Smad4 showed an enhanced TGFβ-mediated EMT as determined by increased expression of vimentin and decreased expression of β-catenin and E-cadherin. TGFβ-mediated invasion was suppressed in Smad4-intact cells as determined by in vitro assays, and these cells showed a reduced metastasis in an orthotopic model of pancreatic cancer. Interestingly, TGFβ inhibited STAT3Tyr705 phosphorylation in Smad4-intact cells. The decrease in STAT3Tyr705 phosphorylation was linked to a TGFβ/Smad4-dependent and enhanced activation of extracellular signal-regulated kinases, which caused an increase in serine phosphorylation of STAT3Ser727. Down-regulating signal transducer and activator of transcription 3 (STAT3) expression by short hairpin RNA in Smad4-deficient cells prevented TGFβ-induced invasion. Conversely, expressing a constitutively activated form of STAT3 (STAT3-C) in Smad4-intact cells enhanced invasion. This study indicates the requirement of STAT3 activity for TGFβ-induced invasion in pancreatic cancer cells and implicates Smad4-dependent signaling in regulating STAT3 activity. These findings further suggest that loss of Smad4, leading to aberrant activation of STAT3, contributes to the switch of TGFβ from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer. [Cancer Res 2008;68(11):4221–8]
Retinoblastoma Function Is Essential for Establishing Lung Epithelial Quiescence after Injury
Authors: Mason-Richie Nicole A. , Mistry Meenakshi J. , Gettler Caitlin A. , Elayyadi Asmaa , Wikenheiser-Brokamp Kathryn A.
Published: June 2008

The retinoblastoma gene product (RB) regulates cell cycle, quiescence, and survival in a cell type–dependent and environment-dependent manner. RB function is critical in the pulmonary epithelium, as evidenced by nearly universal RB inactivation in lung cancer and increased lung cancer risk in persons with germline RB gene mutations. Lung carcinomas occur in the context of epithelial remodeling induced by cytotoxic damage. Whereas the role of RB in development and normal organ homeostasis has been extensively studied, RB function in the context of cellular injury and repair has remained largely unexplored. In the current studies, the RB gene was selectively deleted in the respiratory epithelium of the mouse. Although RB was not required for establishing or maintaining quiescence during lung homeostasis, RB was essential for establishing quiescence during epithelial repair after injury. Notably, aberrant cell cycle progression was sustained for 9 months after injury in RB-deficient lungs. Prenatal and postnatal RB ablation had similar effects, providing evidence that timing of RB loss was not critical to the outcome and that the injury-induced phenotype was not secondary to compensatory alterations occurring during development. These data show that RB is essential for repair of the respiratory epithelium after cytotoxic damage and support a critical unique role for RB in the context of epithelial remodeling after injury. Because human cancers are associated with chronic cellular damage, these findings have important new implications for RB-mediated tumor suppression. [Cancer Res 2008;68(11):4068–76]
MetMAb, the One-Armed 5D5 Anti-c-Met Antibody, Inhibits Orthotopic Pancreatic Tumor Growth and Improves Survival
Authors: Jin Hongkui , Yang Renhui , Zheng Zhong , Romero Mally , Ross Jed , Bou-Reslan Hani , Carano Richard A.D. , Kasman Ian , Mai Elaine , Young Judy , Zha Jiping , Zhang Zemin , Ross Sarajane , Schwall Ralph , Colbern Gail , Merchant Mark
Published: June 2008

The hepatocyte growth factor (HGF) and its receptor, c-Met, have been implicated in driving proliferation, invasion, and poor prognosis in pancreatic cancer. Here, we investigated the expression of HGF and c-Met in primary pancreatic cancers and described in vitro and in vivo models in which MetMAb, a monovalent antibody against c-Met, was evaluated. First, expression of HGF and MET mRNA was analyzed in 59 primary pancreatic cancers and 51 normal samples, showing that both factors are highly expressed in pancreatic cancer. We next examined HGF responsiveness in pancreatic cancer lines to select lines that proliferate in response to HGF. Based on these studies, two lines were selected for further in vivo model development: BxPC-3 (c-Met+, HGF−) and KP4 (c-Met+, HGF+) cells. As BxPC-3 cells are responsive to exogenous HGF, s.c. tumor xenografts were grown in a paracrine manner with purified human HGF provided by osmotic pumps, wherein MetMAb treatment significantly inhibited tumor growth. KP4 cells are autocrine for HGF and c-Met, and MetMAb strongly inhibited s.c. tumor growth. To better model pancreatic cancer and to enable long-term survival studies, an orthotopic model of KP4 was established. MetMAb significantly inhibited orthotopic KP4 tumor growth in 4-week studies monitored by ultrasound and also improved survival in 90-day studies. MetMAb significantly reduced c-Met phosphorylation in orthotopic KP4 tumors with a concomitant decrease in Ki-67 staining. These data suggest that the HGF/c-Met axis plays an important role in the progression of pancreatic cancer and that targeting c-Met therein may have therapeutic value. [Cancer Res 2008;68(11):4360–8]
Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma
Authors: Calvisi Diego F. , Pinna Federico , Meloni Floriana , Ladu Sara , Pellegrino Rossella , Sini Marcella , Daino Lucia , Simile Maria M. , De Miglio Maria R. , Virdis Patrizia , Frau Maddalena , Tomasi Maria L. , Seddaiu Maria A. , Muroni Maria R. , Feo Francesco , Pascale Rosa M.
Published: June 2008

Sustained activation of extracellular signal-regulated kinase (ERK) has been detected previously in numerous tumors in the absence of RAS-activating mutations. However, the molecular mechanisms responsible for ERK-unrestrained activity independent of RAS mutations remain unknown. Here, we evaluated the effects of the functional interactions of ERK proteins with dual-specificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by real-time reverse transcription–PCR and Western blot analysis, were significantly higher in tumors with better prognosis (as defined by the length of patients' survival) when compared with both normal and nontumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to either ERK/SKP2/CKS1-dependent ubiquitination or promoter hypermethylation associated with loss of heterozygosity at the DUSP1 locus. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK, as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1, and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1, or SKP2 potential therapeutic targets for human HCC. [Cancer Res 2008;68(11):4192–200]
Polo-like Kinase 3 Functions as a Tumor Suppressor and Is a Negative Regulator of Hypoxia-Inducible Factor-1α under Hypoxic Conditions
Authors: Yang Yali , Bai Jingxiang , Shen Rulong , Brown Sharron A.N. , Komissarova Elena , Huang Ying , Jiang Ning , Alberts Gregory F. , Costa Max , Lu Luo , Winkles Jeffrey A. , Dai Wei
Published: June 2008

Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In this study, we examined the physiologic function of Plk3 by generating Plk3-deficient mice. Plk3−/− mice displayed an increase in weight and developed tumors in various organs at advanced age. Many tumors in Plk3−/− mice were large in size, exhibiting enhanced angiogenesis. Plk3−/− mouse embryonic fibroblasts were hypersensitive to the induction of hypoxia-inducible factor-1α (HIF-1α) under hypoxic conditions or by nickel and cobalt ion treatments. Ectopic expression of the Plk3-kinase domain (Plk3-KD), but not its Polo-box domain or a Plk3-KD mutant, suppressed the nuclear accumulation of HIF-1α induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1α expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1α in mediating the activation of the “survival machinery” in cancer cells, these studies strongly suggest that enhanced tumorigenesis in Plk3-null mice is at least partially mediated by a deregulated HIF-1 pathway. [Cancer Res 2008;68(11):4077–85]
Laforin Confers Cancer Resistance to Energy Deprivation–Induced Apoptosis
Authors: Wang Yin , Liu Yan , Wu Cindy , McNally Beth , Liu Yang , Zheng Pan
Published: June 2008

A long-standing but poorly understood observation in experimental cancer therapy is the heterogeneity in cancer susceptibility to energy deprivation. Here, we show that the hexose kinase inhibitor 2-deoxyglucose (2-dG) preferentially kills cancer cells with defective laforin expression and significantly increases the survival of mice with aggressive lymphoma due to a genetic defect of the laforin-encoding Epm2a gene. Normal cells from Epm2a−/− mice also had greatly increased susceptibility to 2-dG. Thus, laforin is a novel regulator for cellular response to energy deprivation and its defects in cancer cells may be targeted for cancer therapy. [Cancer Res 2008;68(11):4039–43]
Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound
Authors: Wald David N. , Vermaat Hanna M. , Zang Shaolei , Lavik Andrew , Kang Zizhen , Peleg Gil , Gerson Stanton L. , Bunting Kevin D. , Agarwal Munna L. , Roth Bryan L. , Tse William
Published: June 2008

As the pathophysiology of acute myelogenous leukemia (AML) involves a block of myeloid maturation, a desirable therapeutic strategy is to induce leukemic cell maturation to increase the efficacy and to avoid the side effects of traditional chemotherapeutics. Through a compound library screen, 6-benzylthioinosine (6BT) was identified as a promising differentiation-inducing agent. 6BT induces monocytic differentiation of myeloid leukemia cell lines such as HL-60 and OCI-AML3, as well as primary patient samples as evidenced by morphology, immunophenotyping, and nitroblue tetrazolium reduction. Not only can 6BT induce differentiation but a subset of AML cell lines such as MV4-11 and HNT34 instead undergo 6BT-mediated cell death. Despite inducing cell death in some leukemic cells, 6BT exhibits extremely low toxicity on several nonmalignant cells such as fibroblasts, normal bone marrow, and endothelial cells. This toxicity profile may relate to the function of 6BT as an inhibitor of the nucleoside transporter, ent1, which is thought to prevent it from entering many cell types. In contrast, 6BT likely enters at least some leukemic cell lines as shown by its requirement for phosphorylation for its differentiation activity. 6BT is also able to synergize with currently used myeloid differentiation agents such as ATRA and decitabine. Early studies indicate that the mechanism of action of this compound may involve ATP depletion that leads to growth inhibition and subsequent differentiation. Besides in vitro activity, 6BT also shows the ability to impair HL-60 and MV4-11 tumor growth in nude mice. 6BT is a promising new monocytic differentiation agent with apparent leukemic cell–specific activity. [Cancer Res 2008;68(11):4369–76]
Chromosome Instability and Risk of Squamous Cell Carcinomas of Head and Neck
Authors: Wang Li-E , Xiong Ping , Zhao Hui , Spitz Margaret R. , Sturgis Erich M. , Wei Qingyi
Published: June 2008

In 895 subjects with squamous cell carcinoma of the head and neck (SCCHN) and 898 cancer-free controls matched by age, sex, and ethnicity, we validated our previous finding that mutagen sensitivity as measured by the frequency of chromatid breaks in vitro induced by benzo[a]pyrene diol epoxide (BPDE) is an independent risk factor for SCCHN. Using a previously established concentration of 4 μmol/L BPDE to treat short-term cultured primary lymphocytes for 5 hours, we evaluated chromatid breaks in 50 well-spread metaphases for each blood sample. The mean frequency of BPDE-induced chromatid breaks was significantly higher in cases than in controls in non-Hispanic Whites (P = 0.0003) but not in other ethnic groups (P = 0.549 for Hispanic Americans and 0.257 for African Americans). The odds ratio associated with risk of SCCHN for the frequency of chromatid breaks greater than median value of controls was 1.56 (95% confidence interval, 1.27–1.91) in non-Hispanic Whites (767 cases and 763 controls) after adjustment for age, sex, smoking status, and drinking status. When the quartiles of the controls were used as the cutoff values, there was a dose response between the degree of mutagen sensitivity and risk of SCCHN in non-Hispanic Whites (Ptrend = 0.0001). However, none of these associations in non-Hispanic Whites was identified in Hispanic Americans (69 cases and 70 controls) or African Americans (59 cases and 65 controls), possibly because of the small samples of these ethnic groups or ethnic difference in genetic variation, which needs to be confirmed in future studies. [Cancer Res 2008;68(11):4479–85]
WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth
Authors: Wang Liangyou , Sloper Daniel T. , Addo Sadiya N. , Tian Defeng , Slaton Joel W. , Xing Chengguo
Published: June 2008

Patients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (−)-gossypol. Overexpressing Bcl-2 or Bcl-XL failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3–induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC. [Cancer Res 2008;68(11):4377–83]
Guggulsterone, a Farnesoid X Receptor Antagonist, Inhibits Constitutive and Inducible STAT3 Activation through Induction of a Protein Tyrosine Phosphatase SHP-1
Authors: Ahn Kwang Seok , Sethi Gautam , Sung Bokyung , Goel Ajay , Ralhan Ranju , Aggarwal Bharat B.
Published: June 2008

Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6–induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein and mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G1 phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells. [Cancer Res 2008;68(11):4406–15]
Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice
Authors: Dineen Sean P. , Lynn Kristi D. , Holloway Shane E. , Miller Andrew F. , Sullivan James P. , Shames David S. , Beck Adam W. , Barnett Carlton C. , Fleming Jason B. , Brekken Rolf A.
Published: June 2008

Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non–tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. [Cancer Res 2008;68(11):4340–6]
Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression
Authors: Karp Cristina M. , Tan Ting Ting , Mathew Robin , Nelson Deidre , Mukherjee Chandreyee , Degenhardt Kurt , Karantza-Wadsworth Vassiliki , White Eileen
Published: June 2008

Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]
Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth
Authors: Montgomery R. Bruce , Mostaghel Elahe A. , Vessella Robert , Hess David L. , Kalhorn Thomas F. , Higano Celestia S. , True Lawrence D. , Nelson Peter S.
Published: June 2008

Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription–PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59–0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03–0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447–54]
RET/PTC-Induced Cell Growth Is Mediated in Part by Epidermal Growth Factor Receptor (EGFR) Activation: Evidence for Molecular and Functional Interactions between RET and EGFR
Authors: Croyle Michelle , Akeno Nagako , Knauf Jeffrey A. , Fabbro Doriano , Chen Xu , Baumgartner Jacqueline E. , Lane Heidi A. , Fagin James A.
Published: June 2008

RET/PTC rearrangements are one of the genetic hallmarks of papillary thyroid carcinomas. RET/PTC oncoproteins lack extracellular or transmembrane domains, and activation takes place through constitutive dimerization mediated through coiled-coil motifs in the NH2 terminus of the chimeric protein. Based on the observation that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 decreased RET/PTC kinase autophosphorylation and activation of downstream effectors in thyroid cells, despite lacking activity on the purified RET kinase, we proceeded to examine possible functional interactions between RET/PTC and EGFR. Conditional activation of RET/PTC oncoproteins in thyroid PCCL3 cells markedly induced expression and phosphorylation of EGFR, which was mediated in part through mitogen-activated protein kinase signaling. RET and EGFR were found to coimmunoprecipitate. The ability of RET to form a complex with EGFR was not dependent on recruitment of Shc or on their respective kinase activities. Ligand-induced activation of EGFR resulted in phosphorylation of a kinase-dead RET, an effect that was entirely blocked by PKI166. These effects were biologically relevant, as the EGFR kinase inhibitors PKI166, gefitinib, and AEE788 inhibited cell growth induced by various constitutively active mutants of RET in thyroid cancer cells as well as NIH3T3 cells. These data indicate that EGFR contributes to RET kinase activation, signaling, and growth stimulation and may therefore be an attractive therapeutic target in RET-induced neoplasms. [Cancer Res 2008;68(11):4183–91]
TIP30 Induces Apoptosis under Oxidative Stress through Stabilization of p53 Messenger RNA in Human Hepatocellular Carcinoma
Authors: Zhao Jian , Chen Jingjing , Lu Bin , Dong Li , Wang Huajing , Bi Chongshan , Wu Guobin , Guo Huaizu , Wu Mengchao , Guo Yajun
Published: June 2008

Reactive oxygen species (ROS) and cellular oxidant stress have long been associated with cancer. Here, we show that TIP30, also called CC3, regulates p53 mRNA stability and induces apoptosis by sensing of intracellular oxidative stress in human hepatocellular carcinoma (HCC) cells. Introduction of TIP30 induced more cell death in HepG2 cells with a high level of intracellular ROS than that in normal liver cell line, HL7702, which had low level of intracellular ROS. Treatment with an antioxidant agent attenuated TIP30-induced cell death in HepG2 cells, whereas oxidant H2O2 augmented TIP30-induced cell death in HL7702 cells. The conformation of TIP30 was altered with the formation of an intermolecular disulfide bridge under oxidative stress. TIP30 greatly enhanced p53 expression and its transcriptional activity under oxidative stress, which was probably through stabilization of p53 mRNA. TIP30 induced apoptosis and mitochondrial dysfunction were blocked by silencing of p53 expression. The nuclear import of mRNA-binding protein HuR was blocked upon TIP30 introduction, which might be due to the interruption of the association of HuR with importin β2. The elevated cytoplasmic HuR bound to p53 mRNA 3′-untranslated region, resulting in prolonged half-life of p53 mRNA. Our results suggest that TIP30 is involved in cellular oxidative stress surveillance and induces apoptosis through stabilization of p53 mRNA in HCC cells. [Cancer Res 2008;68(11):4133–41]