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We will never conquer cancer until we find a way to keep it from spreading

Amato GiacciaAmato Giaccia, PhD

Alan Yatagai, photographer

Science writers anthropomorphize the behavior of cancer as it spreads, likening malignant cells to marauding barbarians who run amok, colonizing and ultimately destroying the body.

To an extent, this description is apt. Cancerous tumor cells flaunt growth controls and invade normal tissues. Some tumor cells proliferate wildly by hijacking genes and enzymes involved in wound healing. Others roust genes that normally retire after embryonic development. After subverting those genes, cancer cells multiply and establish beachheads in foreign, potentially harsh locales.

But as it turns out, metastasis, which is responsible for 90 percent of deaths from solid tumors, is not chaotic. An emerging body of research from the laboratory of Amato Giaccia, PhD, shows that malignant tumors collude with their environment to dispatch cancer cells far and wide.

And now he’s fingered one protein he’s convinced is the Achilles heel of metastasis. Giaccia’s excited about the implications of his research for people with cancer.

“We envision that instead of being a fatal illness, cancer will become a chronic condition like diabetes or arthritis,” says Giaccia, professor of radiation oncology.

Giaccia notes that some of the greatest successes in cancer therapy have been in the treatment of blood malignancies – cancers without tumors – such as leukemias, lymphomas and Hodgkin’s disease. Researchers also can offer effective treatments for certain germ cell cancers, such as testicular cancer. But few cures exist for the majority of solid tumors.

The lowdown on oxygen

In 1955 scientists first realized solid tumors have extremely low oxygen (hypoxic) levels. The most aggressive cancers originate from hypoxic sites, and hypoxia decreases the effectiveness of chemotherapy and even surgery.

In 1996 at Stanford, Giaccia speculated whether hypoxia and other factors in the tumor’s environment imposed a strong selective pressure on tumor cells to adapt to their austere surroundings. Research published in 1990 by Richard Hill, PhD, senior scientist at the Ontario Cancer Institute, had hinted at this by showing that tumor hypoxia increased the production of genes that control metastasis.

Further scrutiny of how hypoxia affects gene activity in tumor cells led to a finding that could be cancer’s undoing. In 2003 Nicholas Denko, PhD, then a postdoctoral fellow in the Giaccia lab (and now assistant professor of radiation oncology at Stanford), conducted a gene microarray experiment to gain insight into how genes alter their expression in response to oxygen. Denko showed that in tumors, hundreds of genes change their activity when oxygen is low.

In poring over the list of genes whose activity increased under hypoxic conditions, the researchers consistently found the gene lysyl oxidase (LOX) elevated in many different tumor types. They hypothesized that LOX might a play an important role in tumor cell migration and perhaps even metastases.

Finding a target

It was January 2004 and Janine Erler, PhD, had just begun her work in the Giaccia lab. Like every new post-doc, she received a list of hypoxia-regulated genes and a command to select the one that interested her and explain why.

She picked LOX because of new research showing LOX was present in aggressively metastatic cell lines.

“It made sense to me that if oxygen-deprived cancer cells were more invasive and metastatic, and they also have high levels of LOX, it may be that LOX is responsible for the increased invasive capacity,” says Erler.

Giaccia, Erler and colleagues have since shown that inhibiting the LOX protein significantly impedes and sometimes even eradicates malignant growth in animal cancer cells and in human cancer cells transplanted into mice – and causes no negative side effects. In cases where metastasis already exists, blocking LOX keeps cancer spread in check. On the other hand, cancer patients with heightened levels of LOX have decreased survival, the group found.

Giaccia’s lab further explored the power of LOX by seeing what would happen if they took LOX out of the tumor milieu. In an experiment using tumor cells taken from human breast, head and neck, pancreas and lung, they blocked production of LOX and then transplanted those cells into mice. They found that the LOX-less cells led to decreased invasion and incidence of metastasis.

The lab used additional strategies to remove LOX: targeting LOX with a hypoxia-activated inhibitor and with an anti-LOX antibody – both developed in the Giaccia lab. This reduced the formation and growth of metastases and significantly increased the survival of animals with metastatic disease. There were no negative side effects in mice that received anti-LOX therapy.

Because LOX is “tumor agnostic” – not unique to one type of solid tumor but present in all hypoxic tumors – a LOX-inhibiting drug may offer an obvious advantage in being able to treat a wide range of tumors.

Giaccia suggests that anti-LOX therapy could be combined with chemotherapy and/or radiotherapy – an antimetastatic “cocktail” – to target both a primary tumor and metastasis. His group is also developing hypoxia-targeted substances that selectively amplify the effects of radiation and chemotherapy on tumor cells while sparing normal cells.

Measurement of LOX levels in the blood might eventually be used in the clinic as a prognostic and diagnostic marker of metastasis, Giaccia says.

Highway to metastasis

One of LOX’s normal roles is to help form and stabilize the extracellular matrix, which, in addition to acting as a mini-scaffold, regulates how cells communicate with each other.

But Giaccia’s group has identified another, more sinister role for the protein: LOX secreted by hypoxic primary tumor cells helps recruit the immature bone marrow cells that power metastatic growth. LOX also interacts with fibronectin, a protein that binds cells to the extracellular matrix and holds cells together to form tissues. Fibronectin acts as rigging for LOX and increases LOX activity.

In hypoxic conditions in tumors, where excess amounts of LOX are produced, cells are directed to build a “highway to metastasis” for tumor cells to move through the body and to prepare a “pre-metastatic niche,” or future site of cancer spread.

LOX’s role in establishing the pre-metastatic niche was discovered by Giaccia, Erler and post-doc Kevin Bennewith, PhD, with Stanford radiation oncology faculty members Edward Graves, PhD; Albert Koong, MD, PhD; and Quynh-The Le, MD.

Exploiting hypoxia-induced genes

Though most efforts in cancer research are focused on ways to eradicate primary tumors, the majority of deaths from cancer result from metastasis. And in some cancers, such as pancreatic, metastasis is usually under way by the time a primary tumor is first detected.

But new research findings indicate that strategies targeting hypoxia-related proteins could turn this around, says Giaccia. For example, his studies have launched clinical tests of the hypoxia-related protein known as connective tissue growth factor (CTFG). In animal studies, the inhibiting CTFG stops the spread of pancreatic cancer. A clinical study in humans is scheduled to begin at Stanford later this year.

Work in the Giaccia lab is emblematic of a new area of molecular medicine called “theranostics,” in which the disease marker is also the therapeutic target, and the activity of drug targets in the patient’s tissue or blood can be measured.

His research group has identified several other genetic markers of hypoxia that, like LOX and CTFG, may help predict tumor recurrence and survival in a number of solid tumors. In ongoing experiments, they are exploring the use of these markers as potential targets for diagnosis, prognosis and cancer therapy.

But while current technologies can determine whether disease is present, they cannot assess ongoing activity of prospective drug targets in a patient’s biopsy. In response to this need, Ted Graves, with Giaccia, Erler, Bennewith and post-doctoral scholar Christine Ham, MD, is developing noninvasive imaging techniques to provide assessment of tumor hypoxia and response of a tumor and surrounding cells to treatment.

“With our expanding range of imaging, we can now assess in real time how a drug is working – anatomically, using CT [computerized tomographic] scanning, and functionally, with PET [positron emission tomography],” Graves notes.

Graves believes molecular imaging will enable cancer researchers to tailor treatment for each patient that is based on molecular pathways of the tumor and its environment.

“The ability to identify secreted proteins induced by tumor hypoxia will help predict tumor relapse and survival in cancer patients. It also will stimulate the clinical trial and drug development process,” Graves says.

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