When Isaiah J. Fidler, D.V.M., Ph.D., left his veterinary surgical practice to pursue a doctorate that would allow him to study and combat the lethal spread of cancer to other organs, he got lots of advice. The common message: Don't go there.
“I was told by very serious scientists that I should stay out of the field because cancer metastasis is the pinnacle of chaos, of randomness,” Fidler said.
Fidler plunged ahead with research that exposed the origins of metastasis, the processes by which these cells spread and thrive in other organs, the molecular diversity that makes them so hard to treat, and the crucial supporting role of their surrounding microenvironment.
“Nothing in biology is random, there are only processes that we don't understand,” Fidler said. “Metastasis is, in fact, a highly regulated process every step of the way.”
For his basic science discoveries and contributions to the treatment of cancer metastasis, Fidler earned the 2013 American Cancer Society Medal of Honor for Basic Research. Professor in The University of Texas MD Anderson Cancer Center Department of Cancer Biology and director of its Metastasis Research Laboratory, Fidler was honored at the ACS 100th anniversary celebration in Atlanta on May 22.
Tumor environment critical to metastasis
“To say this honor is richly deserved is an understatement. Dr. Fidler wasn't just in on the ground floor of metastasis research, he was instrumental in building it,” said MD Anderson President Ronald DePinho, M.D.
“Two major areas of cancer research today address the importance of the tumor microenvironment and the genetic diversity, or heterogeneity, of cancer cells. Both fields have roots in Josh Fidler's research,” DePinho said. “His current work expands our knowledge of brain metastasis and uncovers new potential treatments for that lethal condition.”
Fidler expressed elation and gratitude. “I am deeply honored to receive this award and I share this recognition with colleagues, collaborators and trainees who worked diligently and creatively to uncover the vital details of metastasis,” he said.
Fidler also praised MD Anderson's dedication to translational research, moving laboratory discoveries through the final steps that result in clinical trials of new therapeutic options via close collaboration with clinicians. “I've been doing translational research all of my life,” he said.
A new potential approach to metastatic brain tumors
His current research addresses cancers that spread to the brain, which occur in about 170,000 U.S. patients annually, are virtually untreatable and relatively under-studied.
Treatment of brain metastases has been thought to be hindered by the blood-brain barrier, tight construction of blood vessels that protect the brain from toxins in the bloodstream. That barrier is intact in a healthy brain, Fidler said, but the vasculature of tumors is inherently leaky.
“The blood-brain barrier is just an excuse, something else had to be hindering treatment,” Fidler said. Astrocytes are supportive cells that connect to neurons to provide oxygen and sugar and to evacuate waste.
“The problem is these idiots do the same thing for tumors, both primary and metastatic types,” Fidler said. Brain tumors are surrounded and invaded by astrocytes. It's a classic case of an organ's microenvironment aiding cancer survival.
Experiments showed that treating metastatic brain cancer cells in the lab with seven types of chemotherapy killed the cells. Culturing the same cell lines with astrocytes made them highly resistant to all of the drugs.
When an astrocyte touches a tumor cell, it launches expression of hundreds of survival-related genes. Block the connection and nothing happens. The team identified targetable receptors on tumor cells that can be inhibited without affecting neurons. The approach has gone to a phase I clinical trial for brain tumor patients in cooperation with a Swiss drug company.
Experiments spell out the basics of metastasis
Fidler launched his graduate work at the University of Pennsylvania in the mid-1960s with a simple question. If cancer cells were so aggressive, why did scientists have to inject a million cells into a lab animal to get a single tumor?
He injected 100,000 traceable melanoma cells into mice and then observed their travels and activity. “The cells reached every organ in the body,” Fidler said. After several weeks, all of them died except for a few hundred in the lungs, where metastasis took hold.
“It was clear from the beginning that a cell just reaching an organ wasn't enough to establish metastasis,” Fidler said. This experiment established that metastasis arises from less than 1 percent of tumor cells.
Metastatic cells exist in original tumor's diversity
To determine the origin of metastatic cells, Fidler teamed with his wife, the immunologist Margaret Kripke, Ph.D., who suggested they borrow an experimental method used in immunology to identify resistant bacteria.
They took clones of individual cells from a parental tumor, and placed each single cell in a separate culture to grow into a cell line. The resulting cells lines were injected separately into 20 genetically identical mice.
The majority caused no metastasis, a few matched the minimal metastasis of the parental tumor and a handful produced hundreds of metastases.
“This showed that the metastatic cell pre-exists in the diversity of cells in the original tumor,” Fidler said. “And it provided the first proof that tumors are heterogeneous, until then no one used the term.”
A subsequent chromosomal analysis showed that tumor cells are inherently more genetically unstable than normal cells, and that metastatic cells are the most unstable of all.
Seed and soil
The next question was why tumor cells take hold and grow in some organs but not others. Ian Hart, a post-doctoral fellow in his lab, introduced Fidler to the work of Stephen Paget, a 19th century British physician who analyzed hundreds of autopsies of cancer patients and found patterns of metastasis to other organs. His findings were published in the very first issue of The Lancet in 1892.
Paget wrote that tumor cells are like seeds and organs like soil and only when the right seed lands in the right soil will a metastasis thrive. “In essence, everything I had done confirmed Paget's hypothesis,” Fidler said.
Hart and Fidler transplanted mouse embryonic lung and kidney tissue in the flanks of genetically identical mice. They injected radioactively labeled melanoma cells. Cells gathered in many organs, but only took hold in the lungs and in the lung tissue on the mouse's flank.
The findings confirmed the seed-and-soil hypothesis, which is predominant today, and undermined other theories that metastasis was based on blood flow (i.e. to lungs) or perhaps proximity to the original tumor.
“The heterogeneity of metastatic cancer cells means that single-agent targeted therapies will fail against metastatic disease,” Fidler said. “And we ignore the tumor microenvironment at our peril.” Metastasis causes about 85 percent of cancer deaths.
Fidler, known to friends as Josh, also holds the R. E. “Bob” Smith Distinguished Chair in Cell Biology. He came to MD Anderson in 1983, serving as the founding chair of the department of cancer biology until 2008. He is a past president of the American Association for Cancer Research; the world's oldest and largest organization dedicated to cancer research, and was inducted this year into the AACR Academy. Fidler also is a fellow of the American Association for the Advancement of Science.
Fidler also won the Nature Publishing Group's 2010 Lifetime Achievement Award.
An accomplished mentor and teacher, Fidler has mentored 140 scientists, including graduate students, post-doctoral fellows, clinical fellows and visiting scientists.
SOURCE University of Texas MD Anderson Cancer Center