Advancing Discovery and Its Application

Signatures of the Cancer Cell and Its Microenvironment

The Opportunity

Thirty years ago, cancer was a poorly understood and usually deadly disease. This is no longer the case. Today, we have a far better understanding of how cancer develops and progresses within the human body. Over the past three decades - a golden age for scientific discovery in cancer research - scientists have determined that a cell becomes malignant as a result of changes to its genetic material and that accompanying biological characteristics of the cell also change. These changes are unique molecular "signatures" and serve as signals of the presence of cancer. This more robust understanding of the genetic alterations that occur within a cancer cell has changed the course of cancer research and has fueled new approaches to prevention, detection, diagnosis, and treatment.

However, the cancer cell is only part of the story in cancer development. As a cancer cell grows within the elaborate architecture of the body's tissues and organs, it interacts with its surrounding environment. Mounting evidence now suggests that a dynamic interaction occurs between the cancer cell and its local and systemic microenvironment, with each profoundly influencing the behavior of the other. This "tumor microenvironment," is populated with a variety of different cell types, is rich in growth factors and enzymes, and includes parts of the blood and lymphatic systems. It promotes some of the most destructive characteristics of cancer cells and permits the tumor to grow and spread.

The microenvironment can also influence the access of therapeutic agents to tumor cells, the body's processing of treatment agents, and the development of resistance to cancer treatments. Although the cells in the microenvironment may not be genetically altered, their behavior can be changed through interactions with tumor cells. Physicians now realize that they confront a tumor entity that consists of malignant cells combined with their host tumor environment when treating a cancer patient. The tumor cells and their surrounding environment both need to be fully characterized in order to understand how cancer grows in the body, and both need to be considered when developing new interventions to fight it.

Six years ago, NCI established the "Defining the Signatures of Cancer Cells" Extraordinary Opportunity to promote research aimed at identifying and characterizing the full compendium of signature changes that occur within cancer cells. Now, as increasing evidence suggests that the host microenvironment plays a pivotal role in cancer development, we need to expand our effort to consider how the interaction of the cancer cell and microenvironment permits, and even encourages tumor development. Scientists pursuing this promising new scientific opportunity will read not only the signatures of cancer cells but also signatures of seemingly normal cells within the tumor microenvironment and signatures that reflect changes that occur as cancer cells interact with the host microenvironment.

NCI's long-range goal is to extend signatures research to characterize the interaction among a tumor, its microenvironment, and the entire body. All of these signatures of cancer provide important clues for detection, diagnosis, and prognosis and are potential targets for preventive or therapeutic interventions.

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Progress in Pursuit of Our Goal

Through a variety of ambitious initiatives, cancer researchers are making important progress as they probe the DNA of premalignant and malignant cells to identify cancer signatures and test these unique identifiers for their value as early detection and diagnostic biomarkers. Evolving technologies are enabling cancer researchers to look beyond altered genes and determine how their defective protein products disrupt the normal activities of a cell and cause cancer. For example, microarray analysis and sophisticated bioinformatics tools are enabling us to identify previously invisible patterns of active genes and proteins that distinguish specific cancers. Animal models that mimic the development and progression of human cancers are allowing us to study cancer within a whole organism. These technologies will also be used to broaden the scope of signatures research to analyze the signatures of normal cells that interact with cancer cells and constitute the host microenvironment. NCI continues to be instrumental in all these research realms, creating and funding programs that are making invaluable contributions to signatures research.

The Cancer Genome Anatomy Project (CGAP), launched six years ago, is a critical vehicle for coordinating data and reagents that will support advances in molecular detection and diagnosis. The central goal of this project is to provide a complete picture of all the major molecular changes that occur during cancer development. The public data and informatics tools available through CGAP enable researchers to find "in silico" answers to biological questions in a fraction of the time it once took in the lab.

• Through the Tumor Gene Index (TGI), CGAP has now generated more than 8 million gene tags (ESTs) from a wide variety of tumor types and their normal counterparts. Scientists are incorporating these ESTS into the design of microarrays and other technologies that will be used to classify tumors according to their molecular features. These molecular classification strategies hold the potential to improve cancer prevention, early detection, diagnosis, and treatment.
• CGAP's Cancer Chromosome Aberration Project (CCAP) was established to generate a human cancer chromosome aberration map - a genetic map that defines distinct chromosomal alterations associated with cancer. In 2002, investigators accomplished their initial goal, completing a map that integrates structural mapping of the human genome with chromosomal maps. This milestone achievement provides an important resource toward the molecular characterization of chromosomal aberrations associated with cancer.
• Full-length complimentary DNA clones are important tools for defining the sequence and function of genes expressed in human cells. Generating these clones, however, requires a considerable investment of an investigator's time and funds. The NIH Mammalian Gene Collection(MGC), for which CGAP plays a leadership role, was created to generate individual full length human and mouse DNA clones for more rigorous study of individual genes, their protein products, and the role they play in human genes. The MCG has now identified potential full-length clones for more than 20,000 human genes and 11,000 mouse genes. Like all CGAP data and resources, the MGC resources are publicly accessible to the biomedical research community.
• CGAP's Genetic Annotation Initiative (GAI) focuses on exploring and applying technology to identify and characterize sequence variations, known as genetic polymorphisms, in genes important in cancer. A genetic polymorphism, which can affect a gene's function, can arise when mutation causes a change in even a single nucleotide of the DNA. Single nucleotide polymorphisms (SNPs) are important markers for cancer risk-related genes and also can be used to understand difference in vulnerability to cancer among individuals in a population. The CGAP SNP500Cancer project, a new GAI effort, will sequence and make available to researchers 102 samples for known or newly discovered SNPs of immediate importance to molecular epidemiology studies in cancer.

Because genes are the templates for proteins and it is the malfunction of proteins that causes the cell to lose control of its growth process, scientists are turning to proteomics, the study of protein expression and function in living cells. Until recently, researchers have been limited to deciphering the molecular complexities of cancer by studying one, or perhaps a few proteins at a time. With emerging innovations in laboratory technology and artificial intelligence, however, scientists now are able to study patterns of genes and proteins in normal, pre-cancerous, and cancerous cells. Hopefully, this will achieve the next level of understanding of cancer.

In 2001, NCI and the Food and Drug Administration launched the Clinical Proteomics Program (CPP) to apply proteomics advances directly to patient care. CPP investigators are pursuing a number of projects to achieve earlier detection of cancer through minimally invasive testing, individualized diagnosis and treatment strategies, determination of risks and benefits of treatments in the laboratory before use on patients, and enhanced understanding of tumors at the protein level, leading to molecular targeted therapies for cancer.

NCI's Biomedical Proteomics Program is supporting these efforts through its Mass Spectrometry Center (MSC). The MSC is a newly developed state-of-the-art facility that employs several powerful new technologies to cleanly separate proteins and characterize their activities in cancer cells.

Proteomic studies also will be aided by a technology recently developed by investigators funded through the Innovative Molecular Analysis Technologies (IMAT) program. This new technology combines a laser to release proteins directly from the surface of tissue sections with mass spectrometry to accurately identify and localize proteins in cells and tissues. This technology, which has been used successfully to image the location of proteins in tissue sections from human glioblastoma, prostate, and colon tumors, should provide new insights into molecular interactions within a cell. It promises to be a valuable tool in the search for detection, diagnostic, and treatment markers.

The Tissue Array Research Program (TARP), a collaborative effort between the National Human Genome Research Institute and NCI, is a key resource to allow researchers to test interesting genes discovered in profiling studies. The TARP laboratory has produced more than 4,000 tissue microarray slides containing a variety of tumor and normal tissue samples. In a joint effort with the CPP, the TARP laboratory has also developed a cost-effective and user-friendly "cryo-array" platform that can be used to build arrays from very small tumor samples.

The Early Detection Research Network (EDRN) is a comprehensive, collaborative program that merges genetics with proteomics to provide a systematic view of how the molecular signatures of specific cancers can be used as unique, identifying markers. Through EDRN, NCI has created a national research infrastructure in which researchers from multiple institutions work together to identify, develop, and validate early detection markers. EDRN scientists have already discovered a number of novel biomarkers for breast, colon, lung, and prostate cancer using genomic and proteomic approaches and continue to pursue a variety of other promising investigations.

NCI and EDRN scientists are jointly developing a proteomic profile for early detection of breast cancer based on the discovery of a protein profile in blood and breast fluid samples that distinguishes women without breast cancer from women with early, curable breast tumors. Researchers plan to test the protein profile defined by this study to determine its use as a marker for early detection of breast cancer. The same proteomics technology is also being tested for its applicability to detection of ovarian, prostate, and lung cancers. In a preliminary clinical trial of ovarian cancer, investigators were able to correctly identify ovarian cancer in all of 60 women with the disease. Out of 66 patients known not to have cancer, 63 (or 97 percent) were correctly identified as cancer free. Although the accuracy of this test must be improved before it can be used to screen women in the general population, these are exceptionally promising preliminary results.

Through the Director's Challenge: Toward a Molecular Classification of Tumors initiative, investigators are developing profiles of molecular changes in human tumors using DNA, RNA, or protein-based analysis strategies to complement the current tumor classifications that are based on microscopic features with classification schemes based on the molecular alterations of the cancers. Three groups of Director's Challenge investigators - using different experimental approaches - have identified expression profiles that differentiate early lung adenocarcinomas with a poor prognosis from adenocarcinomas that respond favorably to treatment. Although these tumors have different clinical behaviors, they cannot be distinguished from each other by their microscopic appearance.

The ability to differentiate these tumors may help to distinguish between patients who are cured by surgery and do not need further treatment from those who may benefit from more aggressive, or eventually, targeted interventions. The profiles may also reveal previously unknown molecular changes that can be tested as potential targets of new treatments. Director's Challenge investigators have also reported new classification schemes for breast cancer and are working to develop new classification schemes in many other tumor sites. These results demonstrate the power of comprehensive molecular analyses in revealing insights into a tumor's molecular profile, information that one day may guide a physician's decision about the treatment course for individuals patients.

The Mouse Models of Human Cancers Consortium (MMHCC), a large initiative focused on developing and making available to researchers validated mouse models that mimic human cancers, is a vital part of cancer signatures research. With these models, scientists can identify and characterize cancer-associated molecular changes in complete organisms. Recently, several studies using MMHCC-developed prostate cancer mouse models demonstrated that changes in both tumor cells and cells in the microenvironment contribute to tumor progression. Growth factor signals are sent and received by cells in the tumor microenvironment. Based on this information, a group of researchers have engineered a new animal model lacking a specific growth factor in the tumor microenvironment to explore how growth factor loss may affect tumor progression. They also are studying mice engineered to over-express growth factors in either tumor or microenvironment cells to define the impact of these factors on tumor initiation. Finally, they are using mice with an intact signal system to design strategies to interrupt the signals as potential therapy.

The Program for the Assessment of Clinical Cancer Tests (PACCT) facilitates the translation of new knowledge about cancer and new technologies into clinical practice. A Strategy Group, which guides the PACCT, has developed statistical designs for trials of markers that predict response to particular therapies. The Group also has developed an algorithm for developing new prognostic and predictive tests. Working groups will identify promising markers for node negative breast and colon cancer and determine what steps need to be taken, according to the algorithm, to move these markers into clinical practice. In addition, a PACCT funding initiative has been developed to facilitate clinical trials to evaluate melanocyte tumor classification, molecular predictors of oral cancer and the use of nipple aspirate to assess breast cancer risk.

The Plan - Signatures of the Cancer Cell and Its Microenvironment

Accelerate our progress in understanding the dynamic interaction between cancer cells and their microenvironment and our application of this knowledge to the detection, diagnosis, prevention, treatment, and control of all cancers.

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Better Understanding the Cell Microenvironment Holds Promise for More Effective Cancer Treatment and Prevention

For many years, scientists have conducted studies of cells by removing them from their natural surroundings, assuming that the proteins, accessory cells, and blood vessels within a cell's immediate surroundings - its microenvironment - provide nourishment and support with little effect on the cell's function. Over the last two decades, studies have revealed that this assumption is far from accurate. Scientists now know that a cell and its microenvironment have a dynamic and intimate relationship. In the embryo, this relationship ensures that organs develop properly. In the adult, it helps to maintain the stable environment needed for cell functioning and influences a host of cell activities, such as proliferation and programmed cell death.

The cell-microenvironment relationship also plays an important role in cancer development, progression, and spread. When a lone cancer cell arises from multiple changes in its own genes, it does not pose a threat to the body. However, when it progresses to a tumor mass, which is comprised of both cancer cells and cells from the surrounding environment, it becomes a serious health concern. A growing body of evidence suggests that the interaction between cancer cells and their microenvironment is key to this transition. Researchers have observed that:

• The abundance of growth factors in the microenvironment provides a readily available source of growth-promoting signals to tumor cells.
• The influence between the environment and tumor cells is bi-directional. Non-cancerous cells that adjoin a cancerous tumor often take on atypical characteristics and exert a profound influence on a cancer cell's ability to develop into a tumor. Scientists have yet to determine whether these neighboring cells lose their natural capacity to suppress tumor cell growth or whether they acquire an attribute that permits tumor growth.
• An enzyme induced in inflammatory cells found in the tumor microenvironment appears to be the elusive "angiogenic switch," that turns on the normal process of angiogenesis to trigger the formation of new blood vessels. Cancer cells exploit angiogenesis and generate blood vessel formation to gain the nutrients and growth factors needed for continued growth and motility throughout the body.

Scientists now realize that events outside the cancer cell are as important to disease development as the disrupted processes inside the cell. This broadened concept of cancer has taken us from focusing exclusively on the cancer cell to exploring how the interplay between the cancer cell and its immediate environment supports tumor growth. Ultimately, this will enable us to explore the effect of tumor growth on the entire body. This new perspective also opens new avenues to treatment. Rather than targeting the cancer cell alone, new treatment approaches can potentially target the features of the microenvironment that allow tumors to develop and progress. In addition, because the microenvironment often exerts considerable influence over tumor cells in the early stages of tumor development, it promises to be an attractive target for prevention efforts.

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