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Old 09-26-2015, 11:36 PM   #1
Lani
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Lightbulb big step towards preventing metastasis of breast cancer!

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University of California San FranciscoADVANCED


Metastatic Breast Cancer Cells Turn On Stem Cell Genes

Research Suggests Potential Drug Targets to Halt Cancer’s Spread

By Nicholas Weiler on September 23, 2015

It only takes seconds: one cancerous cell breaks off from a tumor, slips into the bloodstream and quickly lodges elsewhere in the body. These colonizers may bloom into deadly metastatic cancer right away or lie dormant for years, only to trigger a recurrence decades after the primary tumor is removed.

Metastases cause the vast majority of cancer deaths, but their tiny seeds are so difficult to track that few researchers have managed to study them. Now, scientists from UC San Francisco describe capturing and studying individual metastatic cells from human breast cancer tumors implanted into mice as the cells escaped into the blood stream and began to form tumors elsewhere in the body.

The researchers discovered that genetic programs expressed in these cells were quite distinct from the primary tumors in which they originated and included genes typically expressed in mammary stem cells. The findings, published online Sept. 23 in Nature, could change the way researchers think about how cancer spreads and suggest new drugs to track down and disable its deadly seeds.

For the most part, modern cancer drugs ignore differences between primary and metastatic tumors, said Zena Werb, PhD, professor and vice-chair of anatomy at UCSF, and a senior author on the new study.

“We test drugs for their ability to make primary tumors shrink, but most just don't work on metastases, and this leaves patients open to recurrence,” Werb said. “Patients have their original tumor treated or removed, but then the cancer comes back 20, 30, 40 years later because there were just a few metastatic cells sitting around.”

Catching metastatic cancer cells in the act

No one really knows how dormant metastatic cells can survive incognito for decades, said Devon Lawson, PhD, who led the research team as a UCSF post-doctoral researcher and is now an assistant professor of physiology and biophysics at UC Irvine.

“It's a big black box in the cancer field – mostly because it's very difficult to study,” she said.

As a result, Lawson said, only about 7 percent of all breast cancer funding goes to studying metastatic cancer, despite the fact that it causes virtually all breast cancer deaths.

Previous work by Werb’s group had found a subset of cells at the edges of breast cancer tumors that seemed primed to metastasize. Their close contact with the bloodstream and with proteins in the surrounding tumor microenvironment seemed to turn on genetic programs akin to those of mammary stem cells – the cells that allow breasts to form during puberty and grow during lactation. These genes for self-replication could make these cells particularly apt to generate new tumors elsewhere in the body. But the researchers had yet to catch the cells in the act.

In the new paper, the researchers used a technique called patient derived xenograft (PDX), which involves transplanting human tumor cells into mice. Against the backdrop of healthy mouse tissue, rogue metastatic cells from the human tumor stick out like flares. The researchers developed a new method using flow cytometry that let them capture individual human metastatic cancer cells traveling through the mouse’s blood or lodged elsewhere in its body, then used newly-developed microfluidic technology to characterize the active genes in these rare cells.

“We were able to look at gene expression at a whole new level of resolution,” Lawson said. “We could pull 12 metastatic cells out of the brain and tell you what is special about those 12 cells. Or the two cells we found in the blood. And we discovered there's something really unique about metastatic cells as they arrive in distant tissues.”

Metastases show stem cell qualities

The team compared patterns of gene expression in human cancer cells lodged in different organs of the PDX mice and found stark differences between early-stage and more advanced metastatic colonies. In metastases that had already grown and spread throughout an organ, the cancer cells’ gene activity looked much like that of the primary tumor that had been transplanted into the mice, though with subtly different features specific to the new organ, whether lymph, liver, lung or brain.

In contrast, early-stage metastases and cancer cells traveling through the blood expressed genes typically active in mammary stem cells and quite distinct from primary tumor cells. In addition, these seed cells expressed specific genes that would be expected to keep them in a dormant, undifferentiated state and relatively immune to cell death, which the researchers surmised might help metastatic colonies survive in new and hostile environments.

Remarkably, the same signature pattern of gene activity was found in metastatic cells in mice whose tumors came from genetically and clinically diverse human patients. In other words, the genetic program that makes a cell metastatic did not depend on the genetics of its tumor of origin – suggesting that new techniques might allow researchers to find and specifically target these cells throughout the body in a variety of patient populations.

Insights could lead to targeted therapies

The research team performed a proof of principle experiment to demonstrate how valuable information about metastatic gene expression could be for drug development. Since metastatic cells that were beginning to differentiate into secondary tumors showed high expression of genes cMYC and CDK2, the researchers treated 24 PDX mice with dinaciclib, a CDK inhibiting drug known to kill off cells with high MYC levels. Whereas 44 percent of control mice (11 of 25) developed secondary tumors within four weeks, researchers could only find metastatic cells in one drug-treated mouse (4 percent).

Werb emphasized that this test was just a proof of principal and that dinaciclib itself may or may not prove be the ideal drug to target metastases. The key point, she said, was that the drug managed to nearly eliminate metastases without shrinking the primary tumor.

“If this drug had only been tested on primary tumors, we would have said it doesn't work,” she said. “This tells us you actually have to look at metastases if you want drugs that treat them.”

Preventing metastatic cells from invading other parts of the body has been a priority for cancer researchers for many years, said Andrei Goga, MD, PhD, professor of cell and tissue biology, and of medicine at UCSF and a co-corresponding author on the new study. “But practically speaking, by the time you’ve detected the tumor, that horse is either already out of the barn or it isn’t. This new study is exciting because if you know the genetics of these early metastatic cells you can go after them specifically, wherever they are in the body. And that’s the name of the game.”

The researchers say the single-cell genomics they used in this study – which a consortium of researchers at UCSF are applying to diverse biological and clinical questions – could have a major impact on the emerging field of precision medicine.

“It’s definitely a brave new world,” Lawson said. “We couldn’t have done this even five years ago. And this paper is just the tip of the iceberg.”

Major funding for the research was provided by the National Cancer Institute, Stand Up To Cancer and the American Association for Cancer Research, the US Dept. of Defense, the Breast Cancer Research Foundation, the Atwater Foundation, Dave and Julie Vander Wall, and a grant from the Ministry of Science and Technology, Taiwan.

Additional co-authors on the study are Nirav R. Bhakta, MD; Kai Kessenbrock, PhD; Karin D. Prummel, MS; Ying Yu; Ken Takai, MD, PhD; Alicia Zhou, PhD; Henok Eyob, PhD; Sanjeev Balakrishnan; and Chih-Yang Wang, all of UCSF at the time of the research, and Paul Yaswen, PhD, of Lawrence Berkeley National Lab. Kessenbrock is currently at UC Irvine; Prummel at the University of Zürich, Switzerland; and Takai at Biwako Ohashi Hospital, Shiga, Japan.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.
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Old 09-27-2015, 01:29 AM   #2
donocco
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Re: big step towards preventing metastasis of breast cancer!

Intersting.

The anti-diabetic drug Metformin lowers Myc and CDK 4,6 protein levels. Possibly Metformin could have anti-metastasis effects. As long as the renal function is good (serum creatinine in women less than 1.4mg%, men 1.5mg%) it is relatively safe as long as you are monitored carefully by a physician. Maybe more people should consider taking it. Speak with your doctors

Paul

Once the renal function decreases there is a danger of Lactic Acidosis which can be fatal. This is why renal function has to be carefully monitored.
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Old 09-27-2015, 11:54 AM   #3
lkc Gumby
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Re: big step towards preventing metastasis of breast cancer!

very interesting. I decided i wanted to be metformin years ago. basically told my doctor what i found out and asked him to write a script for me. have been on it since with absolutely no problems.

compelling information regarding the benefits on metformin has been out there for years.

alot of docs will not rec., as it is off label....

also it's super super cheap, so no money to be made for the biggie companies.
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Dxed Stage IIIC May 05, 12 pos nodes
er/pr -neg,Her -pos
LVI
Right partial mast & partial axillary dissection-June14,2005
Right modified mast-no clear margins- June 30, 2005
DD AC x4
Taxotere X4 with Herceptin
Rads x 35( 5 fields )
Left prophylactive mast( atypia & hyperplasia found ),
put on Tamoxifen x 1 yr; D/ced due to endometrial thickening
bilateral recon (saline implants)May 06
Nipple recon July 06
metformin 2010
removal of implants due to severe encapsulation, insertion of gummies 2013
Reclast Q yr
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Old 11-11-2015, 11:20 AM   #4
v-ness
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Re: big step towards preventing metastasis of breast cancer!

i find this at once fascinating, exciting and yet chilling. thinking how micro-mets can just hide out for decades? ugh. an office-mate just got a recurrence in the same place in her breast 12 yrs after her original breast cancer. i am excited about the work in genetics and wish that more money would go toward study of mets. thank you, lani!
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8/09 - IDC 1.8 cm triple positive, lumpectomy left breast
10/09 began chemo (taxotere & carboplatin) and weekly herceptin.
1/21/10 finished chemo, continued on herceptin every 3 weeks until 10/2010.
2/10 began 7 wks of radiation
6/10 mom dies of primary peritoneal ovarian cancer
8/10 got my last remaining ovary out
10/10 mammogram all clear
3/11 MRI shows 5 'spots' in right breast, largest 1 cm unidentifiable on US
needle biopsy proved the largest to be old inflamed cyst -phew!
7/10 switched to Arimidex
8/9 switched to Femara - allergic to arimidex
Femara made me lose hair quickly so switched to Aromasin
Aromasin made my hair fall out too and the bone pain was too much.
back on Tamoxifen 1/2013.
blood clot from trains and planes 5/2014 so on coumadin per onco for as long as i am on tamoxifen
tamoxifen was supposed to be up with my 5 yrs in may but my boyfriend was diagnosed with stage 4 colon cancer so i am staying on tamoxifen indefinitely because i want some ammo against BC, given the stress. lost my husband in only 10 wks in 2007 to stage 4 esophageal cancer.
cancer's screwing with another man i love
2/2016 - 6yrs in remission, off tamoxifen and off coumadin - yay!
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Old 11-12-2015, 04:41 AM   #5
Bunty
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Re: big step towards preventing metastasis of breast cancer!

Because of reading other posts on this site about Metformin, I spoke to my oncologist recently about putting me on it. I fully expected him to roll his eyes and sigh, and said as much to him before broaching the subject. But he was more than interested, as he has had one other metastatic patient approach him about it, and because they insisted, he put them on it. I think because I raised it with him, he said he was going to do some further investigation, and when I next met with him, we would discus putting me on Metformin.
Marie
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dx Dec 2000 dcis 2.5cm clear sentinel node, ER/PR- Her-2+
lumpectomy, 6 cycles AC, 6 weeks rads
October 2007 three x 2.5cm lung mets. 8 months Taxol, started Herceptin and continue. Significant reduction in lung mets.
June 2011 3cm x 4cm liver tumour. Started Abraxane and continue with Herceptin.
November 2011. Finished with Abraxane, continue with just Herceptin. Liver tumour now reduced to 15mm x 12mm. Lung tumour now 10mm x 0.5mm
February 2012. Scans show everything stable, and brain scan clear.
July 2012. PET/CT scans show I'm in remission - no active cancer!
]Dec CT brain cllear, lungs stable, liver tumour has increased to 20mm. PET scans showed active liver met and active lung thinglet, and possible bone met.
Jan 2013 recommence Abraxane, continue with Herceptin.
June 2013 finish Cycle 6 Abraxane, continue with Herceptin. 30% reduction in liver tumour, everything stable.
December 2013. CA15-3 on rise.
February 2014. PET and CT scans show single liver tumour has increased to 35mm. No other activity.
March 2014. Planned for SBRT for liver met, but couldn't have treatment as tumour too close to bowel. Continue Herceptin.
April 2014. Surgeon advises that I am a good candidate for liver resection, so will have operation early May (after camping holiday). Tumour now 44mm x 29mm.
May 7, 2014. Two liver tumours surgically removed. Third of liver removed, and gall bladder. Am I NED?May 2014. Pathology of tumour shows it's now ER+ (95% staining).
June 2014. CA15-3 has decreased to 18 from a pre-surgery reading of 59!
June 2014. Started Femara, continue with Herceptin.
July 2014. Stop Femara due to severe Osteoporosis. Commence Tamoxifen, continue Herceptin. Waiting to hear if I can have Aclasta infusion.
August 2014. CA15-3 has decreased further to 12 - YAY!
October 2014. Aclasta infusion for Osteoporosis. November 2014, CA15-3 decreased to 11. Scans of liver all clear, something new showing up on lung, but just watching at the moment.
November 2015. Started SBRT on solitary lung met.
November 2015. Bone density scan showed very good improvement so back on Femara - yay!
December 2016. 6 treatments of SBRT radiation on lung. Seems to have had some effect.
June 2016. CA15-3 still stable and low at 9.
June 2016. Started subcutaneous Herceptin replacing infusion.
Jan 2017. LVEF dropped to 46%. Stopped Herceptin.
Feb 2017. Started ACE Inhibitor and BETA Blocker. Still off Herceptin.
Aug 2017. Two new mets - Portacaval lymph node and mediastinal lymph node.
Aug 2017. Blood tests show extremely elevated liver enzyme levels. Many tests to investigate.
Sept 2017. Portacaval lymph node blocking liver bile duct causing liver enzyme and Bilirubin problems.
Oct 2017. 8cm stent inserted into liver bile duct. Procedure caused pancreatitis, and hospitalised for 3 days. Liver enzymes improving rapidly.
Nov 2017. Commenced 4 weeks of radiation on Portacaval lymph node. 5 week break before chemo.
Jan 2018. CT scan. 11 new small liver mets, and new superclavical lymph node med.
Jan 2018. Start Kadcyla. CA15-3 426.
Apr 2018. First scans since starting Kadcyla. All tumours reducing. CA15-3 dropped to 30 from 426.
Dec 2019. Still on Kadcyla, but two small brain mets have been treated in the past month with SRS. CA15-3 stable for 12 months at 11.
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Old 11-12-2015, 06:48 PM   #6
europa
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Re: big step towards preventing metastasis of breast cancer!

I have been on the Metformin trial for a few years with no problems. It's a very easy drug to tolerate I find. Other than the metallic taste it can giv water.
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DX 10/2011
PET Scan + MRI 10/2011
Lumpectomy 11/11/11
Stage 2B +++ ER+(10%), PR+(5%), HER2+++(1 positive node, 1 micromets to second node)
AC started 12/2011 ended 1/2012
Taxol + Herceptin weekly for 12 weeks ended 4/2012
30 zaps of radiation done 6/2012
Tamoxifen 6/2012
every 3 weeks of Herceptin for another year.
Metformin Trial 8/12
10/12 MRI- CLEAR
01/13 BRAIN MRI- CLEAR!
01/13 Neck MRI- CLEAR!
FINISHED HERCEPTIN 1/9/2013...Woot Woot
Starting Walter Reed Vaccine Trial 2/13
CT Scans + ultrasound of abdomen CLEAR-5/13
02/2015 through 11/2015 emergency D&Cs for Tamoxifen induced uterine polyps which caused uncontrollable hemorrhaging
12/2015 blood clot to left leg caused by Tamoxifen. No longer taking it. On Xarelto, a blood thinner
12/2015 Ablation to prevent hemorrhaging from potential issues with Tamoxifen residue in my system
1/2016 continuing journey without hormonal therapy. Reevaluating the option of a hysterectomy and oopherectomy.
4/1/2018 2mm stroke. Yes, stroke! No cause ever found but they believe it was a migraine that went bonkers and created a tiny clot. No deficits. I was back to normal with 24hrs. Now on baby aspirin for life.
7/27/2018 hysterectomy and oopherectomy
01/07/2019 Mastectomy and expanders put in
3/22/2019 Vtach, almost died. Cause unknown.
7/22/2019 New perky boobs put in
7/21/2020 Off of all drugs but a baby aspirin because of the stroke in 2018.


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8 YEARS NED
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