UNDERSTATING HOW CANCER METASTASISE

The latest findings on how cancer cells metastasize from primary to distant sites are highlighted in a special issue of Science, published on April 8.

The special issue contains a number of reviews and perspective articles that outline the latest advances in understanding the process of metastasis, and also how it could be stopped, a journal press release explains.

"These are critical insights, as metastatic disease remains largely incurable and represents the main cause of cancer-related deaths," it adds.

How tumors change genetically as they grow and then metastasize is covered in a review from two researchers in the United Kingdom, Samra Turajlic at The Royal Marsden Hospital in London, and Charles Swanton at University College London Hospitals and Cancer Institute in London.

"Studying the genetic similarities and differences between primary tumors and their metastases has the potential to shed light on the origin, route, direction, and timing of metastatic spread," the journal notes.

This review discusses intratumoral heterogeneity (the existence of genetically distinct cells in different regions of the primary tumor) and the main clinical implication of this finding — the need for multiple biopsy samples — as previously reported by Medscape Medical News.

It also discusses the data that have been collected across different cancer types that show that metastases can follow several different patterns. "The data suggest that metastasis-competent cells can arise both early in tumorigenesis (the so-called "parallel progression model") and late in tumorigenesis (the so-called "linear progression model").

A new finding highlighted in this review is the idea that cells derived from the primary tumor can work both competitively and cooperatively with each other during metastasis, sometimes even reseeding the original tutor.

Another new insight into the behavior of tumor cells is that they can act collectively rather than as single cells (which is the more conventional view). This is discussed in a perspective article by Kevin Cheung at the Fred Hutchinson Cancer Research Center in Seattle, and Andrew Ewald at the Johns Hopkins University School of Medicine in Baltimore. They discuss recent data from mouse models that "indicates that tumor cells can invade local tissue as a group, circulate through the blood as a group, and seed growth at a distant site as a group," the journal notes.

Tumors Excrete Exomes, But What do They do?

One still controversial finding is the tumors that excrete exomes, miniature vesicles packed with proteins and RNAs, which appear to help facilitate the spread of cancer by priming distant areas of the body to be cancer-cell-friendly, as described in a news story by Jocelyn Kaiser. First discovered 10 years ago and still considered by some to be "passive trash bags," the scientist who made the discovery — David Lyden at Weill Cornell Medicine in New York City — has become convinced that exomes "prepare metastatic sites by changing tissue so it can nourish tumor growth long before cancer cells arrive."

If this theory is correct, then tests for blood-borne tumor exosomes might provide a warning that a cancer is about to metastasize, and there is also the possibility that drugs targeting these vesicles could thwart the growth of metastatic tumors, the article explains

However, it also cites skeptics. Raghu Kalluri of the University of Texas M.D. Anderson Cancer Center in Houston, who also studies the vesicles, says: "It's an open book still. Nothing is completely proven about exosomes and metastasis." Another researcher notes that "there is a disconnect between the animal studies and what is seen in the clinic.... Joan Massagué, a metastasis researcher at Memorial Sloan Kettering Cancer Center in New York City, explains that by the time most patients' cancers are discovered and the primary tumor removed, a few metastatic cells have usually spread and lodged in other organs, where they can lie dormant for years, then awaken and grow. In that case, Massagué argues, it's not clear what role exosomes from a primary tumor that is no longer present would have."

Also arriving before metastatic cancer cells are neutrophils, as described in a another perspective article by Thomas Tüting at University Hospital Magdeburg in Germany, and Karin de Visser at the Netherlands Cancer Institute in Amsterdam. They describe studies showing that "neutrophil accumulation occurs in tissues prior to the arrival of metastatic cancer cells, and that this accumulation is initiated by signals emanating from the primary tumor," the journal notes. Here again, there is potential for therapeutic intervention; several strategies to inhibit neutrophils have shown some success in animal studies, the authors note, and such approaches could be combined with anticancer drugs, they suggest.

Hypoxia in the Metastatic Process

The role that hypoxia (low oxygen conditions) plays in promoting multiple steps of the metastatic cascade is discussed in a second review article, by Erinn Rankin and Amato Giaccia, both from the Stanford University Medical Center in Stanford, California.

Clinically, hypoxia and the expression of a hypoxia-inducible transcription factor (HIF) are associated with increased distant metastasis and poor survival, they explain.

This review details how "cancer cells can harness the hypoxia signaling pathway driven by HIF to adapt to the different environments they encounter during metastasis...[how they] also use HIF signaling to manipulate surrounding immune cells, to the tumor's advantage...[and how they] utilize HIF to help create a 'metastasis friendly' niche in the metastatic site such as bone," the journal notes.

One practical aspect from this research is the recent identification of a receptor tyrosine kinase, AXL, as a critical mediator of HIF-dependent invasion and metastasis, which could in the offer a target for drug manipulation in the future.

AXL is also important in the development of resistance to anticancer therapy, another group of researchers report in the same issue of the journal. This group, with lead author Ital Tirosh from the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, used single-cell sequencing technology to examine the full spectrum of cell types present in metastatic melanoma, identifying a subset of cells that developed resistance to therapy. The journal notes that "AXL is a marker that is associated with resistance to anticancer therapy, and the researchers found that, pretherapy, cancer cells expressing high levels of AXL were mixed with cells expressing relatively low levels of the marker; yet, biopsies of tumors after anticancer treatment revealed an overall shift of cells that have AXL expression after therapy."

"As a medical diagnosis, metastasis instills fear," comments an introduction to the special edition. But it adds that "as a biological process, metastasis instills awe."

"Perhaps one day the research inspired by the awe will stamp out the fear," it concludes.