Novel mechanism for cancer metastasis - Hosein Kouros-Mehr

Cancer Paper 4/23/14 Hosein Kouros-Mehr

Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis

Zhou et. a., Cancer Cell, Volume 25, Issue 4, p501–515, 14 April 2014

A recent paper suggests a new mechanism for metastasis of cancer cells to distant organs.  Metastasis is a complex process consisting of a series of steps that a cancer cell must achieve to establish de novo cancers in distant organs.  One of the rate-limiting steps in metastasis is the extravasation and growth of disseminated cells that have reached the vasculature of the distant organ.  Here the disseminated cells face several barriers:  (1) extravasation across the microvasculature of the distant site, including migration through the endothelial cell layer and basement membrane; (2) survival in the new microenvironment of the distant organ; (3) evasion of the immune response in the distant organ.

Zhou et al. suggest that tumor cells can secrete microRNAs to assist them in the metastatic process.  Namely, they suggest that tumors cells can secrete miR-105 into their microenvironment, which targets the ZO-1 tight junction protein gene in endothelials at sites of tumor dissemination.  This allows downregulation of tight junction proteins in endothelial cells, which then allows cancer cells to extravasate into distant organs.  Interestingly, circulating miR-105 was found to predict metastasis in early-stage breast cancer patients.  

New targets/drugs for oncology have traditionally focused on signaling pathways required for primary tumor cell proliferation and growth.  While many new cancer drugs have come to market over the last few decades, the overall survival rate of cancer has not decreased as greatly as expected.  Metastasis is the primary cause of mortality and morbidity in cancer and new drugs that block metastasis may help increase cancer survival rates.

Hosein Kouros-Mehr 

Novel mutations discovered in a form of ovarian cancer Hosein Kouros-Mehr

A recent paper* in Nature Genetics discovered mutations in the SMARCA4 gene in a form of ovarian cancer known as small cell carcinoma of the ovary.  This cancer is highly aggressive and mostly affects young women.  The authors sequenced tumors from 12 patients and discovered loss of function mutations in SMARCA4 in 100% of the patients (probability of that happening by chance is less than 0.0000000000000002).  The importance of this finding is that it may lead to targeted therapies that can be tailored for patients with this disease.  

The SMARCA4 gene is an ATP-dependent helicase that is part of the SWI/SNF complex.  This complex regulates chromatin remodeling and is important for transcriptional activation of genes that may be normally silenced in heterochromatin.  SWI/SNF complex is composed of many proteins and its mechanism of action is largely unknown, but it is thought that SWI/SNF can destabilize histone-DNA interaction in an ATP-dependent manner and lead to chromatin remodeling of target genes, thereby altering the accessibility and transcription of the target genes.  SMARCA4 is a ATP-dependent helicase, which means it helps separate/unwind the strands of DNA using energy derived from ATP hydrolysis.  

The authors found that SMARCA4 mutations in these patients were all loss of function mutations that lead to significantly less SMARCA4 protein in the cells. Interestingly, the overexpression of SMARCA4 in SMARCA4-null cancer cell lines led to suppression of cell growth, suggesting that SMARCA4 is a bona fide tumor suppressor.  The depletion of SMACA4 using lentiviral shRNA knockdown led to increase cell growth in cell lines.  

SMARCA4 mutations are also found in bladder cance, stomach cancer, lung cancer, and glioma (5-8% frequency).  Most of these are missense mutations of uncertain consequence, though lung cancers contained frequent inactivating SMARCA4 mutations.  Further work will be necessary to identify candidate targets for drug discovery in SMARCA4 mutant tumors.  For example, the SMARCA2 ATPase may be upregulated in SMARCA4 mutant tumors and could be a candidate target in this patient population.  Further validation will be necessary to evaluate this potential new target.  

Jelinic, P., et. al.  (2014).  Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.  

Nature Genetics

 

(2014) 

23 March 2014

Hosein Kouros-Mehr

the end of Tech Bubble 2.0? Hosein Kouros-Mehr

Is this the beginning of the end?

We are all familiar with the tech bubble of the late 1990s and crash in the early 2000s.  Could the charts be setting up for a similar tech crash this year?  While it is too early to tell, there are worrisome developments in technology stocks that could easily trigger a correction is not an outright crash over the next 12 months.  While this is a purely technical argument, the Nasdaq has not reached the highs of the 2000s and the animal spirits in today's market do not match those in the earlier bubble.  But it could be the memories of the first tech bubble crash that prevents the rise of the 2nd tech bubble today.

Here is the weekly Nasdaq-100 chart from 1998-2001.  Beginning in October 1998, the Nasdaq-100 spent 17 months above the 20 day weekly moving average and tested it 4 times during that time.  Then came a blow off top with a huge bearish engulfing candle that pierced the 20 day MA in March 2000.  It wasn't until 6 months later that it failed at the 50 day MA and began to crash to pre-rally levels.  The technical damage occurred swiftly and came as a surprise to many.  The wise ones took their money out during the period of consolidation before the crash.




Here is the Nasdaq-100 chart from the last two years. As in the previous chart, the Nasdaq-100 spent 15 months above the 20 day MA and tested it 4 times.  Over the last week it broke through the 20 day MA to the downside.  To continue the uptrend as it stands, the Nasdaq-100 will need to bounce quickly above the 20 day MA and while Janet Yellen may be the one who can do that, it appears that it's time to test the 50 day MA.  While it's too early to say whether "Tech Bubble 2.0" is truly over, caution is warranted in the near term.




Disclaimer:  The content of this blog should not be used as recommendation to purchase or sell securities.
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Hosein Kouros-Mehr

Cancer Archeology paper - Hosein Kouros-Mehr

Interesting article in Plos One describing discovery of metastastic carcioma in a young male who lived in Sudan in 1200 BC.  While not necessarily shedding light into the mechanisms of cancer metastasis, the paper presents interesting novel archeological data that can be used for future historical analyses.  The mechanisms that drive metastasis are likely to be as old as the mechanisms that drive normal development.  

RESEARCH ARTICLE

On the Antiquity of Cancer: Evidence for Metastatic Carcinoma in a Young Man from Ancient Nubia (c. 1200BC)

• Michaela Binder mail,
 
• Charlotte Roberts,
 
• Neal Spencer,
 
• Daniel Antoine,
 
• Caroline Cartwright

• Published: March 17, 2014
• DOI: 10.1371/journal.pone.0090924

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Abstract

Cancer, one of the world’s leading causes of death today, remains almost absent relative to other pathological conditions, in the archaeological record, giving rise to the conclusion that the disease is mainly a product of modern living and increased longevity. This paper presents a male, young-adult individual from the archaeological site of Amara West in northern Sudan (c. 1200BC) displaying multiple, mainly osteolytic, lesions on the vertebrae, ribs, sternum, clavicles, scapulae, pelvis, and humeral and femoral heads. Following radiographic, microscopic and scanning electron microscopic (SEM) imaging of the lesions, and a consideration of differential diagnoses, a diagnosis of metastatic carcinoma secondary to an unknown soft tissue cancer is suggested. This represents the earliest complete example in the world of a human who suffered metastatic cancer to date. The study further draws its strength from modern analytical techniques applied to differential diagnoses and the fact that it is firmly rooted within a well-documented archaeological and historical context, thus providing new insights into the history and antiquity of the disease as well as its underlying causes and progression.

Hosein Kouros-Mehr

Cancer Research Articles of Interest - Hosein Kouros-Mehr

I will be posting one cancer research article per week related to cancer metastasis, immunotherapy, angiogenesis, and pathways related to cell proliferation and apoptosis.

March 21, 2014:

1.  RTEL1 -- Interesting novel target that is frequently amplified in cancers according to TCGA database (publicly available information).  This paper sheds light on its potential mechanism in cancer.

RTEL1: functions of a disease-associated helicase

 

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Trends in Cell Biology, 26 February 2014
Copyright © 2014 Elsevier Ltd All rights reserved.
10.1016/j.tcb.2014.01.004

Authors

Jean-Baptiste Vannier,Grzegorz Sarek,Simon J. BoultonSee Affiliations

• Highlights
• RTEL1 is an Fe–S helicase that controls homologous recombination by dismantling D-loop intermediates.
• RTEL1 maintains telomere integrity by disassembling T-loops and counteracting G4-DNA structures.
• RTEL1 variants strongly associate with predisposition to glioma, astrocytoma, and glioblastoma.
• Mutations in RTEL1 give rise to Hoyeraal–Hreidarsson syndrome.

Hosein Kouros-Mehr