HonCode

Go Back   HER2 Support Group Forums > her2group
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 08-05-2015, 09:49 PM   #1
Lani
Senior Member
 
Join Date: Mar 2006
Posts: 4,776
progress on discovering how cancer begins--but is it the chicken or the egg?

Disrupting Cells’ “Powerhouses” Can Lead to Tumor Growth

Cancer cells defy the rules by which normal cells abide. They can divide without cease, invade distant tissues and consume glucose at abnormal rates.

Now a study by University of Pennsylvania researchers implicates defects in mitochondria, the energy-production centers of cells, as playing a key role in the transition from normal to cancerous. When the Penn scientists disrupted a key component of mitochondria, otherwise normal cells took on characteristics of cancerous tumor cells.

The research, published in the journal Oncogene, was led by members of the lab of Narayan G. Avadhani, the Harriet Ellison Woodward Professor of Biochemistry in Penn's School of Veterinary Medicine's Department of Biomedical Sciences, in collaboration with the lab of Hiroshi Nakagawa from the Gastroenterology Division in Penn's Perelman School of Medicine. Satish Srinivasan, a research investigator in Avadhani's lab, was the lead author.

In 1924, German biologist Otto Heinrich Warburg observed that cancerous cells consumed glucose at a higher rate than normal cells and had defects in their "grana," the organelles that are now known as mitochondria. He postulated that the mitochondrial defects led to problems in the process by which the cell produces energy, called oxidative phosphorylation, and that these defects contributed to the cells becoming cancerous.

"The first part of the Warburg hypothesis has held up solidly in that most proliferating tumors show high dependence on glucose as an energy source and they release large amounts of lactic acid," Avadhani said. "But the second part, about the defective mitochondrial function causing cells to be tumorigenic, has been highly contentious."

To see whether the second part of Warburg's postulation was correct, the Penn-led research team took cell lines from the skeleton, kidney, breast and esophagus and used RNA molecules to silence the expression of select components of the mitochondrias' cytochrome oxidase C, or CcO, a critical enzyme involved in oxidative phosphorylation. CcO uses oxygen to make water and set up a transmembrane potential that is used to synthesize ATP, the molecule used for energy by the body's cells.

The biologists observed that disrupting only a single protein subunit of cytochrome oxidase C led to major changes in the mitochondria and in the cells themselves.

"These cells showed all the characteristics of cancer cells," Avadhani said.

They displayed changes in their metabolism, becoming more reliant on glucose and reducing their synthesis of ATP. Instead of conducting oxidative phosphorylation, they largely switched over to conducting glycolysis, a less efficient means of making ATP that is common in cancer cells.

The cells lost contact inhibition and gained an increased ability to invade distant tissues, both "hallmarks of cancer cells," Avadhani noted. When they were grown in a 3D medium, which closely mimics the natural environment in which tumors grow in the body, the cells with disrupted mitochondria formed large, long-lived colonies, akin to tumors.

The researchers also silenced cytochrome oxidase C subunits in already-tumorigenic breast and esophageal cancer cell lines.

"We found that the cells became even more invasive, heightening their malignant potency," Srinivasan said.

Finally the Penn team looked at actual tumors from human patients and found that the most oxygen-starved regions, which are common in tumors, contained defective versions of cytochrome oxidase.

"That result alone couldn't tell us whether that was the cause or effect of tumors, but our cell system clearly says that mitochondrial dysfunction is a driving force in tumorigenesis," Avadhani said.

The researchers observed that disrupting CcO triggered the mitochondria to activate a stress signal to the nucleus, akin to an "SOS" alerting the cell that something is amiss. Avadhani and his colleagues had previously seen a similar pathway activated in cells with depleted mitochondrial DNA, which is also linked to cancer.

Building on these findings, Avadhani and members of his lab will examine whether inhibiting components of this mitochondrial stress signaling pathway might be a strategy for preventing cancer progression.

"We are targeting the signaling pathway, developing a lot of small molecules and antibodies," Avadhani said. "Hopefully if you block the signaling the cells will not go into the so called oncogenic mode and instead would simply die."

In addition, they noted that looking for defects in cytochrome oxidase C could be a biomarker for cancer screening.

SOURCES:
Oncogene, July 6, 2015
University of Pennsylvania (http://www.upenn.edu)
Lani is offline   Reply With Quote
Old 08-06-2015, 11:59 AM   #2
agness
Senior Member
 
Join Date: Aug 2014
Location: Seattle, WA
Posts: 285
Re: progress on discovering how cancer begins--but is it the chicken or the egg?

I feel like I represent a more unique case study as I had been diagnosed in the past with adrenal dysfunction, had low progesterone during infertility testing (a sign of adrenal stress), and my disease developed while I was doing extended breastfeeding, a massive nutritional draw on my system plus I suffered from chronic dehydration. My magnesijm, ferritin, and zinc were crazy low. My copper was crazy high. My HER2 disease developed without challenge and wasnt discovered until I was stage 3B, but really metastatic.

I think we could learn more about this disease through my body, labs and experience.

This article plays into a deeper understanding of dysregulation in the body.
__________________
  • Dx 2/14 3b HER2+/HR- left breast, left axilla, internal mammary node (behind breast bone). Neoadjuvant TCHP 3/14-7/2. PCR 8/14 LX and SND. 10/21-12/9 Proton therapy to chest wall.
  • Dx 7/20/15 cerebellar met 3.5x5cm HER2+/HR-/GATA3+ 7/23/15 Craniotomy.
  • 7/29/15 bone scan clear. 8/3/15 PET clean scan. LINAC SRS (5 fractions) Sept 2015. 9/17/15 CSF NED, 9/24/15 CSF NED, 11/2/15 CSF NED.
  • 10/27/15 atypical uptake in right cerebellum - inflammation?
  • 12/1/15 Leptomeningeal dx. Starting IT Herceptin.
  • 1/16 - 16 fractions of tomotherapy to cerebellum, break of IT Herceptin during rads, resume at 100 mg weekly
  • 3/2016 - stable scan
  • 5/2016 stable scan
  • 7/2016 pseudoprogression?
  • 9/2016 more LM, start new chemo protocol and IV therapy treatment with HBOT
  • 11/2016 Cyberknife to temporal lobe, HBOT just prior
  • 12/2016 - lesions starting to show shrinkage
  • 8/2017 - Stable since Dec 2016. Temporal lobe lesion gone.
  • Using TCM, naturopathic oncology, physical therapy, chiro, massage, medical qigong, and energetic healing modalities in tandem. Stops at nothing.
  • Mother of 2 boys - ages 7 and 10 (8/2017) and a lovely partner with lots to live for.
agness is offline   Reply With Quote
Old 10-03-2015, 08:35 PM   #3
norkdo
Senior Member
 
norkdo's Avatar
 
Join Date: Jul 2011
Location: ottawa canada
Posts: 367
Re: progress on discovering how cancer begins--but is it the chicken or the egg?

Agness, another one, like myself, who only discovered it in stage 3b. I can't tell you how many people on here discovered their HER2 breast cancer (neg for estrogen and progesterone) only in stage 3b. i know there are lots who caught it earlier but four years ago, when i got it, i scrubbed the posts to read everybody's staging at diagnosis and there was a poll that supported my suspicions. i think the numbers may have changed, who knows, but i want to say how sorry i am you got cancer at your end of the life spectrum instead of later on. especially when childbearing (and therefore a lot of hope) was going on.
__________________
fall 2008: mammo of rt breast worrisome so am asked to redo mammo and have ultrasound of rt breast.I delay it til january 2009 and the results are "no cancer in rt breast. phew."
found plum sized lump in right breast the day before my dad died: April 17th 2011. saw it in mirror, while i was wearing a top, examining my figure after losing 10 lbs on dr. bernstein diet.
diagnosed may 10 2011

mast/lymphectomy: june 7 2011, 5/20 cancerous nodes. stage 3a before radiation oncologist during our first mtg on july 15th says he found cancer on the lymph node of my breast bone. Now stage 3b.
her2+++, EN-, PN-. Rt brst tumors:3 at onset, 4.5 cm was the big one
chemos: 3fec's followed by 3 taxotere, total of 18 wks chemo. sept: halfway thru chemo the mastectomy scar decides to open and ooze pus. (not healed before chemo) eventually with canasten powder sent by friend in ny (illegal in canada) it heals.
radiations:although scheduled to begin 25 january 2012, I am so terrified by it (rads cause other cancers) I don't start til february, miss a bunch, reschedule them all and finally finish 35 rads mid april. reason for 7 extra atop the 28 scheduled is that when i first met my rads oncologist he said he saw a tumor on the lymph node of my breastbone. extra 7 are special kind of beam used for that lymphnode. rads onc tells me nobody ever took so long to do rads so he cannot speak for effectiveness. trials had been done only on consecutive days so......we'll see.....
10 mos of herceptin started 6 wks into chemo. canadian onc says 10 mos is just as effective as the full yr recommended by dr. slamon......so we'll see..completed july 2012.
Sept 18 2012: reconstruction and 3 drains. fails. i wear antibiotic pouch on my job for two months and have 60 consecutive days visiting a nursing centre where they apply burn victims' silver paper and clean the oozing infection daily. silicone leaks out daily. plastic surgeon in caribbean. emergency dept wont remove "his" work. He finally appears and orders me in into an emergency removal of implant. I make him promise no drains and I get my way. No infection as a result. Chest looks like a map of Brazil. Had a perfectly good left breast on Sept 17th but surgeon wanted to "save another woman an operation" ? so he had crashed two operations together on my left breast, foregoing the intermediary operation where you install an expander. the first surgeon a year earlier had flat out refused to waste five hours on his feet taking both boobs. flat out refusal. between the canadian health system saving money and both these asses, I got screwed. who knows when i can next get enough time off work (i work for myself and have no substitute when my husband is on contract) to get boobs again. arrrgh.


I have a blog where I document this trip and vent.
www.nora'scancerblog.blogspot.com . I stopped the blog before radiation. I think the steroids made me more angry and depressed and i just hated reading it anymore
norkdo is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is Off

Forum Jump


All times are GMT -7. The time now is 05:32 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2021, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter