Special issue: Cancer metastasis

This special issue on cancer, largely focused on metastasis, features two Reviews, two Perspectives, an editorial and a news story that highlight the latest advances in understanding how cancer cells spread and the best means by which to prevent this dissemination. These are critical insights, as metastatic disease remains largely incurable and represents the main cause of cancer-related deaths. The special issue also includes a report that provides new insights into how tumors develop resistance to targeted drug treatments.

First, an editorial by Harold Varmus explains how recent steps by the U.S. government to increase funding for cancer research will be valuable for treating advanced cancer. He suggests that more resources should also go into preventative care, and proposes that the government direct the Center for Medicare and Medicaid Services (CMS) to allow reimbursement for molecular profiling of cancers. This, he says, "would vastly increase the data available for analysis, accelerate interpretation of genetic profiles, provide a test bed for true sharing of clinical information, and allow future coverage determinations by CMS to be made more quickly and sensibly."

A feature story from Science's news department, by Jocelyn Kaiser, discusses the emerging evidence that tumors that excrete exomes, miniature vesicles packed with proteins and RNAs, help facilitate the spread of cancer by priming distant areas of the body to be cancer cell-friendly. Initially controversial and still not fully accepted, this theory continues to gain traction.

A Review by Samra Turajlic and Charles Swanton looks at how tumors genetically evolve in the context of metastasis. 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 authors first discuss the confounding role of intratumoral heterogeneity (the existence of genetically distinct cells in different regions of the primary tumor) in interpreting the results of these studies and the need for multiple biopsy samples. They then highlight what has been learned to date from such "phylogenetic" studies across different cancer types. 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"). There are also indications that cells derived from the primary tumor can work both competitively and cooperatively with each other during metastasis, sometimes even re-seeding the original tumor. In general, these conclusions are based on studies of small numbers of patients, and the authors emphasize the need for much larger studies.

A second Review by Erinn Rankin and Amato Giaccia summarizes research on the role that hypoxia (low oxygen conditions) plays in promoting multiple steps of the metastatic cascade. Clinically, hypoxia and the expression of a hypoxia-inducible transcription factor called HIF are associated with increased distant metastasis and poor survival. Cancer cells can harness the hypoxia signaling pathway driven by HIF to adapt to the different environments they encounter during metastasis. Cancer cells also use HIF signaling to manipulate surrounding immune cells, to the tumor's advantage. Furthermore, cancer cells utilize HIF to help create a "metastasis friendly" niche in the metastatic site such as bone. The authors also discuss a recently identified receptor tyrosine kinase, AXL, as a critical mediator of HIF-dependent invasion and metastasis, as well as a potential therapeutic target for metastatic disease.

A Perspective by Kevin Cheung and Andrew Ewald discusses recent studies suggesting that at various stages of the metastatic cascade, tumor cells act collectively rather than as single cells (the more conventional view). Recent work with mouse models 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.

A Perspective by Thomas Tüting and Karin de Visser looks at the role that neutrophils play in metastasis. Neutrophils are immune cells in our blood that are meant to protect us from infections and facilitate wound healing, yet, intriguingly, neutrophils frequently accumulate in cancer patients and are associated with metastasis. Studies have even found 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 authors discuss several strategies to inhibit neutrophils that have shown some success in animal studies, noting that combining therapies that interfere with these immune cells with anticancer therapies may be a viable means to deter metastasis.

Finally, to better understand how cancer cells develop drug resistance, a study by Itay Tirosh et al. employs single cell sequencing technology to examine the full spectrum of cell types present in metastatic melanoma, identifying a subset that develop resistance to therapy. Like other solid tumors, melanomas are "ecosystems" that contain not only malignant tumor cells but nonmalignant cells such as fibroblasts and a variety of immune cells. The researchers analyzed the RNA profiles from 4,645 malignant, immune, and stromal cells isolated from 19 tumors from patients with metastatic melanoma. They identified 229 genes with higher expression in the malignant cells of one region compared with those of other tumor regions. Along with the location of a cancer cell, its levels of exposure to anticancer treatment affected gene expression. AXL is a marker that is associated with resistance to anticancer therapy, and the researchers found that, pre-therapy, 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. The study highlights the importance of both cellular composition and intercellular communication in defining tumor behavior.

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