Month: June 2003

Angiopoietin expression in multiple myeloma

This is an abstract brought to our attention by K.B. on the MM listserv.

Published online July 15, 2003

Blood, 15 July 2003, Vol. 102, No. 2, pp. 417-418

Angiopoietin expression in multiple myeloma

Multiple myeloma demonstrates a progressive, and usually fatal,course, with current treatments generally producing only temporary remissions. Antiangiogenic therapies represent a potential new approach to treating this cancer. While it is well established that growth in solid tumors is dependent on angiogenesis, the role of this process in hematopoietic tumors is not fully appreciated. There is a strong correlation between increased angiogenesis and poor survival in myeloma patients. Furthermore, both cellular and circulating levels of vascular endothelial growth factor (VEGF) are often elevated in hematologic malignancies, including myeloma, and have been shown to predict for a poor outcome, lending additional support to the concept that angiogenic cytokines are involved in the growth and progression of these malignancies.
In this issue, Giuliani and colleagues (page 638) extend our knowledge of marrow angiogenesis with their report on the expression of angiopoietin-1 in myeloma cell lines and patient samples.
Angiopoietin-1 (Ang-1) was found to be expressed in 47% of the patient samples examined. Bone marrow angiogenesis was examined and found to be elevated in 12 of 15 patients examined (80%), and there was a significant correlation between Ang-1 expression and microvascular density (MVD), although no such correlation was present between Ang-1 and Tie2 expression. Giuliani and colleagues were also able to demonstrate that myeloma cells could up-regulate the angiopoietin receptor Tie2 in human bone marrow endothelial cells. Conditioned medium from myeloma cell lines was capable of stimulating angiogenesis, although such stimulation did not occur in the presence of an anti-Tie2 antibody. Angiopoietins, while not believed to be involved in the initial stages of angiogenesis, are known to play an essential role. Ang-1, acting through Tie2, contributes to the stabilization of newly formed vessels via recruitment of peri-endothelial supporting cells as well as endothelial cells, whereas Ang-2, also acting through Tie2, reduces these interactions, leading to vascular regression. It has also been reported that coexpression of Ang-2 and VEGF promotes new vessel sprouting and has been shown to predict a poor prognosis in myeloma and other malignancies.

The role, if any, of angiopoietins in myeloma is far from clear, however. Uneda et al have also recently reported their findings regarding angiopoietin expression in myeloma (Haematologica.
2003;88:113-115). In their study, 27 of 36 multiple myeloma patients studied showed expression of Ang-2 by reverse transcriptase˝polymerase chain reaction (RT-PCR) and immunohistochemistry. Coexpression of VEGF and Ang-2 was detected in 18 of the myeloma samples. The survival rate was significantly lower in those patients expressing Ang-2. Interestingly, and in contrast to the findings by Giuliani et al, they found no evidence of Ang-1 expression.

The seemingly contradictory findings of Ang-1 and Ang-2 expression in these 2 studies should be carefully interpreted in the context of how the cells were isolated and examined. Both studies examined relatively few patients, and in neither study was the effect of the bone marrow microenvironment on expression of these molecules fully taken into account.

Several important outstanding questions remain to be addressed. First, the apparent contradiction in the results from these 2 studies must be resolved. Does expression of Ang-1 or Ang-2 have prognostic value in myeloma? The results from Uneda et al would suggest so. Does angiopoietin expression vary with the stage of the disease? Do the angiopoietins represent valid therapeutic targets? Even if the angiopoietins are not the major driving factors in marrow angiogenesis, the results of Giuliani et al suggest that they may represent a valid target. Although it is too early to answer these questions, the preliminary evidence is tantalizing.

William T. Bellamy
University of Arizona

Related Articles in Blood Online :

Proangiogenic properties of human myeloma cells: production of
angiopoietin-1 and its potential relationship to myeloma-induced
angiogenesis.
Nicola Giuliani, Simona Colla, Mirca Lazzaretti, Roberto Sala,
Giovanni Roti, Cristina Mancini, Sabrina Bonomini, Paolo Lunghi, Magda
Hojden, Giovenzio Genestreti, Mirija Svaldi, Paolo Coser, Pier Paolo
Fattori, Gabriella Sammarelli, Gian Carlo Gazzola, Regis Bataille,
Camillo Almici, Cecilia Caramatti, Lina Mangoni, and Vittorio Rizzoli
Blood 2003 102: 638-645.

Dentist

I’ll be seeing the dentist in July. They have me scheduled for cleanings three times a year instead of the typical two. My dentist wants to keep the bacteria in my mouth under control, since I have an immune system that’s not up to speed. She’s also going to have me take some kind of antibiotic before the cleaning, so the bacteria won’t infect me if it gets into my blood stream as a result of the cleaning.

I think the coumadin must be doing its job. I noticed tonight that my gums bleed pretty freely when I floss now.

Ambien

Ugh! I had a long nap yesterday afternoon, so that disrupted my sleeping schedule. Here I am, wide awake at 4:00 am. I decided to try Ambien. Dr. O. told me to start with 1/2 tablet to see how it works for me. I just took the 1/2 tablet and will see how effective it is. I’m hoping it works. Tonight I’ll be taking dex, so I don’t need an extra sleepless night.

Coumadin

I’m up to 10mg of coumadin a day now. The 8mg dose got my INR to 1.20, and Dr. Orlowski wants it to be between 2 and 3 (closer to 2). I’ll be tested again on Wednesday to see how the 10mg dose is doing. I’m taking coumadin as a preventative for deep vein thrombosis (DVT), which is a possibility for anyone taking thalidomide. There’s more information about DVT at www.dvt.net.

I haven’t been sleeping very well lately. After a few days, it takes its toll, so today I took a xanax about noon and then slept from 1:00 until 5:00. It was fantastic! I fell asleep with the TV on and the notebook computer open on my stomach.

I just remembered something kind of funny. When I saw Dr. Orlowski, he asked me if I vacuumed my ears. Huh? He said I had the cleanest ears he ever saw.

Computers

My IBM Thinkpad crashed in a big way yesterday. I think it’s the hard drive, because it failed to boot. The problem had been developing over the last several weeks, and I ignored it. I did manage to back up some files to CD, but lost all my mail from the last year and a half. I tried to do a “product recovery,” but that wouldn’t even work. The machine just shut down at every attempt. I’ll get a new hard drive for the machine and either use it at the office or sell it. I had to buy another notebook, but in a town like this, there’s not a lot to choose from on short notice. I ended up getting an HP pavilion ze5375. It’s bigger and clunkier than what I’m used to, but I’ll adjust.

Fundraising

If you haven’t yet donated to the MMRF (Multiple Myeloma Research Foundation), you can go online and make your contribution.

MMRF – Donate Online
Fill out the form and be sure to choose “ConnectNC” as the Gift Designation.

Or visit th IMF and make a donation HERE.

Thank you for your help!

Water

My well water doesn’t meet state drinking water standards because of low pH. I’m having it corrected soon. Culligan will be here Monday to install a treatment system, including a tank to correct the pH, a conditioner and a reverse osmosis filter. When it’s all done, I’ll be able to drink the water at the kitchen sink and do away with the bottled water I’ve been having delivered for the last several years.

Friends and family

I want my friends and family to know how grateful I am for their support. Thanks to E for calling several times a day, and to M for checking in at least once a week. Thank you G for taking the time to stay in touch even though your mom passed away. Thanks to D for coming to see me and calling when you can. Thanks S for the email and coming to see me in a few weeks.

Thanks to all my family for tolerating my moods and helping with the things I’m not supposed to do myself anymore. Thanks for driving me to appointments and thanks for getting things for me when I’m sick.

It’s only been 5 months since I was diagnosed, but you have all been there for me before and haven’t abandoned me. I appreciate all that you do, and am forever in your debt.