Treatment-induced damage to tumor microenvironment promotes chemoresistance
Catharine Paddock PhD.
A new study from the US finds that in the process of targeting and killing off cancer cells, chemotherapy may also spur healthy cells in the neighbourhood to release a compound that stimulates cancer growth, eventually leading to treatment resistance. They hope their finding will lead to better therapies for cancer and buy precious time for patients with advanced cancer.
Senior author Peter S. Nelson, of the Human Biology Division at the Fred Hutchinson Cancer Research Center in Seattle, and colleagues, write about their findings in a paper published online on 6 August in Nature Medicine.
Nelson told the media: "Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy."
The reason chemotherapy eventually fails when treating advanced cancer, said Nelson, is because the dose you would need to give the patient to wipe out the cancer would also kill the patient.
In the lab, you can "cure" almost any cancer: you just give a huge dose of toxic chemotherapy to the cancer cells in the petri dish.
But you can't do that to patients, because the high dose would not only kill cancer cells but also healthy cells, said Nelson.
So treatment of common solid tumors has to be given as smaller doses paced out in cycles, to give healthy cells time to recover in the intervals.
But the drawback is that this approach may not kill all the cancer cells, and those that survive can become resistant to subsequent cycles of the chemotherapy.
In their study, Nelson and colleagues found one mechanism through which this can happen.
They studied a type of normal, non-cancerous cell, the fibroblast, that lives near cancer tumors.
In animals, fibroblasts help maintain connective tissue, which is found throughout the body and acts like a "scaffolding" that holds other types of cells and tissue. Fibroblasts are also important for healing wounds and producing collagen.
But under other, non-usual circumstances, they can behave in unexpected ways.
When their DNA is damaged, for instance by chemotherapy, fibroblasts can release a broad range of compounds that stimulate cell growth.
Nelson and colleagues examined cancer cells from prostate, breast and ovarian cancer patients who had been treated with chemotherapy, and found specifically, that when the DNA of fibroblasts near the tumor is damaged by chemotherapy, they start producing a protein called WNT16B in the microenvironment of the tumor.
And, they also found, when the protein reaches a high enough level, it causes cancer cells to grow, invade surrounding tissue, and resist chemotherapy.
"The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression", they write.
Researchers already knew, that the WNT family of genes and proteins are important for growth of both normal and cancer cells, but this study now reveals they may also have a role in promoting treatment resistance.
The researchers saw some WNT proteins increased 30-fold, which was "completely unexpected", said Nelson.
Cancer treatments are becoming increasingly specific, using precise "sniper" approaches to target key molecules rather than general "scatter gun" approaches such as damaging DNA.
The researchers say their findings suggest the microenvironment of the tumor can also play a role in the success or failure of these more precise approaches.
For example, the same cancer cell may react quite differently to the same treatment, in different microenvironments.
They suggest their discovery could help make treatments more effective, for instance by finding a way to block the tumor microenvironment's response.
Professor Fran Balkwill, a Cancer Research UK expert on microenvironments, told the press the study ties in with other studies that show "cancer treatments don't just affect cancer cells, but can also target cells in and around tumors".
Sometimes the effect can be helpful, said Balkwill, giving the example of when chemotherapy triggers health immune cells to attack nearby tumors.
"But this work confirms that healthy cells surrounding the tumor can also help the tumor to become resistant to treatment. The next step is to find ways to target these resistance mechanisms to help make chemotherapy more effective," he added.
Catharine Paddock PhD. "Chemotherapy Can Inadvertently Encourage Cancer Growth." Medical News Today. MediLexicon, Intl., 6 Aug. 2012
"Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B"; Yu Sun, Judith Campisi, Celestia Higano, Tomasz M Beer, Peggy Porter, Ilsa Coleman, Lawrence True & Peter S. Nelson; NatureMedicine, Published online 05 August 2012;DOI:10.1038/nm.2890http://www.nature.com/nm/journal/vaop/n ... .2890.html