Dr. Weeks’ Comment: Here we have MORE confirmation of the merits of Corrective Cancer Care, which addresses the lethal cancer STEM cells while paying less attention to the relatively benign cancer TUMOR cells. So since the lethal cancer STEM cells (which your oncologist is oblivious to) are made more numerous and virulent by chemotherapy and radiation therapy (hence Prof. Max Wicha, M.D. claiming “Chemo and radiation therapy make your cancer worse.“) clearly the current standard of care is violating the first rule of responsible medicine: Primum non Nocere or “First Do No Harm.” What is the answer? As we have told patients and oncologists for the past 5 years, the answer is a safe and effective anti-inflammatory agent. This article suggests Celebrex but we doctors know that this and other NSAIDs are both toxic to kidneys and livers as well as immuno-suppressive at high dosages. But the anti-inflammatory diet is recommended and ground up whole organic seeds from anti-inflammatory plants are tremendously important. Bottom line: the treatment for cancer will soon be understood to be the use of anti-inflammatory agents and chemo and radiation will go the way of the dodo bird. It may take until the current generation of oncologists who only offer “cut burn poison” to die before the new age of “centsible” cancer treatment is widely offered (see Corrective Cancer Care”) but rest assured, once Big Pharma can create highly profitable (patented) anti-inflammatory agents, then that will become the new standard of care. Why not save yourself and your loved ones the torture while today’s doctors catch up with this scientific research and just find a doctor who offers “tomorrow’s medicine today” – you need corrective cancer care.
“… regrowth of cancer stem cells actively contributes to therapy resistance between drug treatment cycles…”
The proposed solution: an anti-inflammatory agent.
“…In studies conducted in mice, the team found that blocking PGE2 abolished the induction of “wound-response” that fuels the regrowth of the cancer stem cells… Celebrex…”
HERE IS AN ANALYSIS
‘Wound response’ of cancer stem cells may explain chemo-resistance in bladder cancer.”
posted by news on December 3, 2014 – 6:30pm
HOUSTON – (Dec. 3, 2014) – A novel mechanism – similar to how normal tissue stem cells respond to wounding – might explain why bladder cancer stem cells actively contribute to chemo-resistance after multiple cycles of chemotherapy drug treatment. Targeting this “wound response” of cancer stem cells can potentially provide a novel approach for therapeutic invention, said researchers from the National Cancer Institute-designated Dan L. Duncan Cancer Center at Baylor College of Medicine.
The results of their study appear online in the journal Nature today.
“Treatment for advanced bladder cancer is limited to surgery and chemotherapy. There are no targeted treatments available,” said Dr. Keith Syson Chan, an assistant professor of molecular and cellular biology and of urology and the corresponding author on the report. “The chemotherapy response is far from ideal so the clinical goal is to advance research into this area and uncover a much more targeted approach.”
Together with co-lead authors Antonina Kurtova, a graduate student in the Translational Biology and Molecular Medicine Program at Baylor, and Dr. Jing Xiao, research assistant in urology at Baylor, Chan and his team sought out to identify mechanisms underlying the development of resistance in bladder cancer that has invaded the muscles. They found that regrowth of cancer stem cells actively contributes to therapy resistance between drug treatment cycles.
“This is a paradoxical mechanism leading to resistance, one we didn’t expect,” said Chan. “The cancer stem cells actively regrow and respond to the induced damage or apoptosis (cell death) caused by chemotherapy in between the different cycles, similar to how normal tissue stem cells respond to wound-induced damages.”
The proliferation is stimulated by the release of a metabolite (or factor) called prostaglandin E2 or PGE2 from the dying cells, which causes the cancer stem cells to repopulate tumors that were reduced in size by chemotherapy, they found.
In normal cells, this is a part of the wound repair process when PGE2 induces tissues stem cells to regrow; in cancer PGE2 ironically induces regrowth of more cancer stem cells in between chemotherapy cycles, Kurtova and Xiao said.
Chan said it is important to note that chemotherapy is administered in multiple cycles, which actually evokes the surprising finding.
“Chemotherapy is applied in one cycle then stopped to allow your bone marrow and normal stem cells to recover from the damage, and then another cycle starts again,” he said. “The cancer stem cells are also recovering during this gap period, induced by PGE2 released from dying cancer cells
“What would happen if you block PGE2?” the researchers asked.
In studies conducted in mice, the team found that blocking PGE2 abolished the induction of “wound-response” that fuels the regrowth of the cancer stem cells.
In one mouse experiment using tumors extracted from a human patient who previously failed chemotherapy, the team observed an enhanced therapeutic response.
“Importantly, we were able to use a drug already approved by the U.S. Food and Drug Administration,” said Kurtova. “This should help us quickly speed up time to start of human clinical trials.”
That drug was Celecoxib or Celebrex®, a drug most commonly used as a treatment for arthritis.
Further study in clinical trials is necessary, but the study provides a promising new find in a type of cancer with no current targeted options, Chan said. Importantly, this treatment may be applicable to other types of solid cancers, he said.
Source: Baylor College of Medicine
HERE IS THE ACTUAL ARTICLE ABSTRACT
Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance.
Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy.
Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.