vendredi 30 novembre 2012

Focus: Histone demethylase GASC1 - a potential prognostic and predictive marker in invasive breast cancer

BACKGROUND: The histone demethylase GASC1 (JMJD2C) is an epigenetic factor suspected of involvement in development of different cancers including breast cancer. It is thought be overexpressed in the more aggressive breast cancer types based on mRNA expression studies on cell lines and meta analysis of human breast cancer sets. This study aimed to evaluate the prognostic and predictive value of GASC1 for women with invasive breast cancer.
All the 355 cases were selected from a cohort enrolled in the Kuopio Breast Cancer Project between April 1990 and December 1995. The expression of GASC1 was studied by immunohistochemistry (IHC) on tissue microarrays. Additionally relative GASC1 mRNA expression was measured from available 57 cases.
In our material, 56% of the cases were GASC1 negative and 44% positive in IHC staining. Women with GASC1 negative tumors had two years shorter breast cancer specific survival and time to relapse than the women with GASC1 positive tumors (p=0.017 and p=0.034 respectively). The majority of GASC1 negative tumors were ductal cases (72%) of higher histological grade (84% of grade II and III altogether). When we evaluated estrogen receptor negative and progesterone receptor negative cases separately there was 2 times more GASC1 negative than GASC1 positive tumors in each group (chi2, p= 0.033 and 0.001 respectively). In the HER2 positive cases, there was 3 times more GASC1 negative cases than GASC1 positives (chi2, p= 0.029). Patients treated with radiotherapy (n=206) and hormonal treatment (n=62) had better breast cancer specific survival when they were GASC1 positive (Cox regression: HR=0.49, p=0.007 and HR=0.33, p=0.015, respectively). The expression of GASC1 mRNA was in agreement with the protein analysis.
This study indicates that GASC1 is both a prognostic and a predictive factor for women with invasive breast cancer. GASC1 negativity is associated with tumors of more aggressive histopathological types (ductal type, grade II and III, ER negative, PR negative). Patients with GASC1 positive tumors have better breast cancer specific survival and respond better to radiotherapy and hormonal treatment.

Source: Histone demethylase GASC1 - a potential prognostic and predictive marker in invasive breast cancer. Berdel B, Nieminen K, Soini Y, Tengström M, Malinen M, Kosma VM, Palvimo J, Mannermaa A ( BMC Cancer. 2012 Nov 14;12(1):516.
Free paper available at:

Focus: ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.

Source: ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C ( J Clin Invest. 2012 Nov 12. pii: 62973.
Free paper available at:

jeudi 29 novembre 2012

Anticancer molecules (100) – Molécules anticancéreuses (100) - RUXOLITINIB


Name: ruxolitinib phosphate
Commercial name: Jakafi
Pharmacological class: small tyrosine kinase inhibitor
Therapeutic class: antineoplastic
Action: ruxolitinib phosphate is a type of tyrosine kinase inhibitor. It.blocks proteins called Janus Kinase (JAK) 1 and 2, which may help keep abnormal blood cells or cancer cells from growing.

In 2012, ruxolitinib phosphate is approved:

for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.


Nom: phosphate de ruxolitinib
Nom commercial: Jakafi
Classe pharmacologique: petite molécule inhibitrice de tyrosine kinases
Classe thérapeutique: antinéoplasiques
Action: le phosphate de ruxolitinib bloque l’activité des tyrosine kinases Janus Kinases 1 et 2 (JAK1 et JAK2), ce qui peut prévenir la prolifération de certaines cellules cancéreuses ou anormales du sang.

En 2012, le phosphate de ruxolitinib est approuvé:

pour le traitement de la myélofibrose à risque élevé ou intermédiaire, incluant la myélofibrose primaire, la myélofibrose, post-polycythemia vera, et la myélofibrose  post- thrombocytémie essentielle.

mercredi 28 novembre 2012

Focus: Host epithelial geometry regulates breast cancer cell invasiveness

Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells. Here we explored how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development, by using a 3D microfabrication-based approach to engineer ducts composed of normal mammary epithelial cells that contained a single tumor cell. We found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining microcomputed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. This work suggests that the mechanical tone of nontumorigenic host epithelium directs the phenotype of tumor cells and provides additional insight into the instructive role of the mechanical tumor microenvironment.

Source: Host epithelial geometry regulates breast cancer cell invasiveness. Boghaert E, Gleghorn JP, Lee K, Gjorevski N, Radisky DC, Nelson CM ( Proc Natl Acad Sci U S A. 2012 Nov 12.
Free paper available at:

Anticancer molecules (99) – Molécules anticancéreuses (99) - AXITINIB


Name: axitinib
Commercial name: Inlyta
Pharmacological class: small tyrosine kinase inhibitor
Therapeutic class: antineoplastic
Action: the orally available axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect.

In 2012, axitinib is approved:

for the treatment of advanced renal cell carcinoma after the failure of one prior systemic therapy.


Nom: axitinib
Nom commercial: Inlyta
Classe pharmacologique: petite molécule inhibitrice de tyrosine kinases
Classe thérapeutique: antinéoplasiques
Action: l’axitinib inhibe l’action des cytokines proangiogéniques “vascular endothelial growth factor” (VEGF) and “platelet-derived growth factor receptor” (PDGF), exerçant par conséquent un effet anti-angiogénique.

En 2012, l’axitinib est approuvé:

pour le traitement du carcinome à cellules rénales avancé, après échec d’une thérapie systémique préalable

mardi 27 novembre 2012

Focus: Prognostic and predictive value of circulating tumor cell analysis in colorectal cancer patients

OBJECTIVE: The aim of this study was to assess the prognostic and predictive values of circulating tumor cell (CTC) analysis in colorectal cancer patients.Patients and methodsPresence of CTCs was evaluated in 60 colorectal cancer patients before systemic therapy - from which 33 patients were also evaluable for CTC analysis during the first 3 months of treatment - through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 (targeting mucin 1 and EpCAM, respectively), followed by real-time RT-PCR analysis of the tumor-associated genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5.
Patients were stratified into groups according to CTC detection (CTC negative, when all marker genes were negative; and CTC positive when at least one of the marker genes was positive). Patients with CTC positivity at baseline had a significant shorter median progression-free survival (median PFS 181.0 days; 95% CI 146.9-215.1) compared with patients with no CTCs (median PFS 329.0 days; 95% CI 299.6-358.4; Log-rank P < .0001). Moreover, a statistically significant correlation was also founded between CTC detection during treatment and radiographic findings at the 6 month staging. This correlation applied to CTC results before therapy (odds ratio (OR), 6.22), 1 to 4 weeks after beginning of treatment (OR, 5.50), 5 to 8 weeks after beginning of treatment (OR, 7.94) 9 to 12 weeks after beginning of treatment (OR, 14.00) and overall CTC fluctuation during the course of treatment (OR, 20.57).
The present study provides evidence of a strong correlation between CTC detection and radiographic disease progression in patients receiving chemotherapy for colorectal cancer. Our results suggest that in addition to the current prognostic factors, CTC analysis represent a potential complementary tool for prediction of colorectal cancer patients' outcome. Moreover, the present test allows for molecular characterization of CTCs, which may be of relevance to the creation of personalized therapies.

Source: Prognostic and predictive value of circulating tumor cell analysis in colorectal cancer patients. Albuquerque A (, Kubisch I, Stölzel U, Ernst D, Boese-Landgraf J, Breier G, Stamminger G, Fersis N, Kaul S. J Transl Med. 2012 Nov 13;10(1):222
Free paper available at:

Focus: An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

Source: An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia. Gruber TA, Larson Gedman A, Zhang J, Koss CS, Marada S, Ta HQ, Chen SC, Su X, Ogden SK, Dang J, Wu G, Gupta V, Andersson AK, Pounds S, Shi L, Easton J, Barbato MI, Mulder HL, Manne J, Wang J, Rusch M, Ranade S, Ganti R, Parker M, Ma J, Radtke I, Ding L, Cazzaniga G, Biondi A, Kornblau SM, Ravandi F, Kantarjian H, Nimer SD, Döhner K, Döhner H, Ley TJ, Ballerini P, Shurtleff S, Tomizawa D, Adachi S, Hayashi Y, Tawa A, Shih LY, Liang DC, Rubnitz JE, Pui CH, Mardis ER, Wilson RK, Downing JR ( Cancer Cell. 2012 Nov 13;22(5):683-97.
Free paper available at:

lundi 26 novembre 2012

Focus: The current status of robotic oncologic surgery

The use of robotic assistance facilitates minimally invasive surgery and has been widely adopted across multiple specialties. This article reviews the published literature on use of this technology for treatment of oncologic conditions. PubMed searches were performed for articles published between 2000 and 2012 using the keywords "robotic" or "robotic surgery" in conjunction with "oncology" or "cancer." Although the most common use for robotics was to treat urologic oncologic conditions, it has also been widely adopted for gynecologic, general, thoracic, and head and neck surgeries. For several procedures, there is evidence that robotics offers short-term benefits such as shorter lengths of stay and lower intraoperative blood loss, with safety profiles and oncologic outcomes comparable to open or conventional laparoscopic approaches. However, long-term oncologic outcomes are generally lacking, and robotic surgeries are more costly than open or laparoscopic surgeries. Robotic technology is widely used in oncologic surgery with demonstrated short-term advantages. However, whether the benefits of robotics justify the higher costs warrant large comparative effectiveness studies with long-term outcomes.

Source: The current status of robotic oncologic surgery. Yu HY, Friedlander DF, Patel S, Hu JC ( . CA Cancer J Clin. 2012 Nov 14.
Free paper available at:



Tumor types are classified according to the International Classification of Diseases for Oncology (ICD-O), 3rd Edition, World Health Organization, Geneva, 2000. The ICD-O-3 is a dual classification and coding system for both morphology and topography of a neoplasm.
The MORPHOLOGY code (Mxxxx/x) indicates the specific histologic term.
The TOPOGRAPHY code (C00-C80) is occasionally mentioned here.

Abbreviation: NOS, not otherwise specified


Les types de tumeurs sont classés en fonction de la « Classification Internationale des Maladies pour l'Oncologie (CIM-O), 3e édition, Organisation mondiale de la Santé, Genève, 2000. La CIM-O-3 est un système de classification et de codage pour la morphologie et la topographie d'une tumeur.
Le code de MORPHOLOGIE (Mxxxx/x) indique le terme spécifique histologique.
Le code de TOPOGRAPHIE (C00-C80) est occasionnellement mentionné ici.

Abréviation: SAI, sans autre indication

M814-M838 Adénomes et adénocarcinomes


Follicular adenocarcinoma, NOS
Adénocarcinome vésiculaire, SAI

Follicular adenocarcinoma, well differentiated
Adénocarcinome vésiculaire bien différencié

Follicular adenocarcinoma, trabecular
Adénocarcinome vésiculaire trabéculaire

Fetal adenocarcinoma

Adénocarcinome foetal

Follicular carcinoma, minimally invasisve
Carcinome vésiculaire microinvasif

Insular carcinoma
Carcinome insulaire



Papillary carcinoma, follicular variant
Adénocarcinome papillaire et vésiculaire

Papillary microcarcinoma
Microcarcinome papillaire

Papillary carcinoma, oxyphilic cell
Carcinome papillaire oxyphile

Papillary carcinoma, encapsulated
Carcinome papillaire encapsulé

Papillary carcinoma, columnar cell
Carcinome papillaire à cellules cylindriques

Medullary carcinoma with amyloid stroma
Carcinome médullaire à stroma amyloïde

Mixed medullary-follicular carcinoma
Carcinome mixte médullaire et vésiculaire

Mixed medullary-paillary carcinoma
Carcinome mixte médullaire et papillaire


Nonencapsulated sclerosing carcinoma
Carcinome sclérosant non encapsulé


Adrenal cortical carcinoma
Carcinome corticosurrénalien



Endometrioid adenocarcinoma

Adénocarcinome endométrioïde

Endometrioid adenofibroma, malignant

Adénofibrome endométrioïde malin

Endometrioid adenocarcinoma, secretory variant

Adénocarcinome endométrioïde, variante sécrétoire

Endometrioid adenocarcinoma, ciliated cell variant

Adénocarcinome endométrioïde, variante à cellules ciliées

Adenocarcinoma, endocervical type

Adénocarcinome de type endocervical