I2 imaging: cancer biology and the tumor microenvironment.

The use of imaging techniques to understand the role of the tumor microenvironment in cancer progression was the topic of a National Cancer Institute (NCI)-sponsored think tank entitled "I2 Imaging: Cancer Biology and the Tumor Microenvironment," held in Alexandria, Virginia on June 8 to 10, 2006. Participants discussed both recent progress in the use of imaging to dissect cellular and molecular interactions within the tumor microenvironment and the challenges that remain. Recommendations made to the NCI included (a) holding an annual meeting at which biologists, clinicians, and imaging scientists could exchange data, facilitating new collaborations within this multidisciplinary field; (b) funding both research and training specifically designed to foster a cross-disciplinary focus; (c) creating and making available a variety of resources to interested investigators, such as a repository of stromal cells and extracellular matrix molecules; and (d) taking steps to encourage translation of the basic research findings into the clinic.

Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

UNLABELLED: ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. INTRODUCTION: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. MATERIALS AND METHODS: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. RESULTS AND CONCLUSIONS: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.

Inflammation in the genesis and perpetuation of cancer: summary and recommendations from a national cancer institute-sponsored meeting.

The Inflammation and Cancer Think Tank Meeting was organized by the National Cancer Institute with the purpose of identifying research advances, gaps, and opportunities for the study and clinical application of the role of inflammation on tumorigenesis. The format of this meeting consisted of brief presentations that focused on concepts, with extensive discussion periods to allow participants to identify issues and barriers limiting progress in this area. The strong relationship between inflammation and cancer in the gastrointestinal tract prompted several presentations that were focused on carcinogenesis within this organ system; however, many of the same immune mediators that influence esophageal, gastric, and colorectal carcinoma were also shown to influence inflammation-related malignancies at other anatomic sites. This article summarizes the findings of this Think Tank Meeting, which highlight the intimate relationship between malignant cells and their inflammatory microenvironment and specifically address opportunities to manipulate the host immune response and therefore intervene at different points along the tumorigenic cascade.

The Tumor Microenvironment at a Turning Point Knowledge Gained Over the Last Decade, and Challenges and Opportunities Ahead: A White Paper from the NCI TME Network.

Over the past 10 years, the Tumor Microenvironment Network (TMEN), supported by the NCI (Bethesda, MD), has promoted collaborative research with the explicit goal of fostering multi-institutional and transdisciplinary groups that are capable of addressing complex issues involving the tumor microenvironment. The main goal of the TMEN was to generate novel information about the dynamic complexity of tumor-host interactions in different organ systems with emphasis on using human tissues and supplemented by experimental models. As this initiative comes to a close, members of the TMEN took time to examine what has been accomplished by the Network and importantly to identify the challenges and opportunities ahead. This consensus document summarizes for the broader scientific community discussions that occurred at the two final meetings of the TMEN in 2015 and 2016. Cancer Res; 77(5); 1051-9. ©2017 AACR.

Extracellular proteolysis and cancer: meeting summary and future directions.

The contribution of extracellular proteolysis to processes of tumor invasion and metastasis has been recognized for more than 20 years. However, after millions of dollars and untold hours of investment in preclinical research and the development of broad range inhibitors of MMPs, clinical trials of late-stage tumor patients show no indication that this approach will be successful. In the basic science arena, there have been stunning advancements that illustrate novel biological activities for proteases and that suggest they are key regulators of many physiological and pathological processes. The Proteases and Cancer: Biology and Therapeutics Workshop (held in Bethesda, MD, November 20-22, 2002) was organized by the Division of Cancer Biology, National Cancer Institute (NCI) to identify research areas and directions that will accelerate understanding protease biology and enhance clinical translation. The overall consensus was that protease biology represents fertile ground for advances that will be clinically useful but perhaps not for the reasons or purpose originally thought. Protease-related technologies show particular promise for the detection, prognosis, and prevention of cancer, and for therapeutic purposes in defined situations. Promising areas for further research are identified, and specific recommendations for the development of a consortium to coordinate the efforts of the protease community are made.

Head and neck cancer: meeting summary and research opportunities.

Head and neck squamous cell carcinoma (HNSCC) is the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract. Nearly two thirds of patients present with advanced (stage III and IV) disease. Fifty percent of HNSCC patients die of their disease, and 5% of HNSCC patients per year will develop additional second primary tumors. Currently used therapeutic modalities (surgery, radiation, and/or chemotherapy) have been associated with rather modest improvements in patient survival. The Head and Neck Cancer: Research and Therapeutic Opportunities Workshop (held in Washington, DC, May 24-26, 2004) was organized by the Division of Cancer Biology at the National Cancer Institute to identify research areas and directions that will advance understanding of HNSCC biology and accelerate clinical translation. The primary goal of the workshop was to identify the barriers that impede basic science discovery and the translation of these developments to the clinical setting. Over a 2.5-day period, experts in both HNSCC and other cancer-related fields met to identify and prioritize the key areas for future research. The overall consensus was that HNSCC is a relatively understudied malignancy and that investigations that focus on the biology of this tumor have the potential to impact significantly on the prevention and treatment of epithelial malignancies. The chief objective is to communicate these research goals to the cancer biology community and encourage more interest in HNSCC as a tumor model to test translational research hypotheses.

Androgens and prostate cancer: are the descriptors valid?

The term androgen-independent cancer has now become a misnomer. Given that the androgen receptor can be activated by even low androgen concentrations or via protein modifications or other protein-protein interactions, a growing prostate cancer has the chance of assuming an androgen depletion-independent state, without necessarily bypassing the androgen signaling processes. It is thus suggested that "androgen-independent (AI)" cancer should be more accurately termed "androgen depletion-independent (ADI)" cancer.

The National Cancer Institute's Efforts in Promoting Research in the Tumor Microenvironment.

The National Cancer Institute has fostered studies of the tumor microenvironment since 1993. Current funding initiatives that span concepts in cancer biology, technology development, convergence of physical sciences-oncology, and systems biology all support research that help in our understanding of the role of the tumor microenvironment at all stages of cancer progression and therapeutic resistance.

Cell-to-cell communication in cancer: workshop report.

Recent advances in cancer biology and the development of new research tools have enabled interrogations of single cells and cell-cell interactions. Emerging technologies are capable of revealing data on the physical characteristics of cells, differences in the genome and proteome between cancerous and healthy cells, and variations in distinct cell subpopulations. Dynamic measurements enable studies that can reveal the evolution of cell characteristics. Cells can also be assembled in vitro or ex vivo into two- and three-dimensional cell environments, allowing for studies of cell-cell interactions and cell signaling. The Memorial Sloan Kettering Cancer Center, in collaboration with the Breast Cancer Research Foundation and the National Cancer Institute, co-organized a workshop as an opportunity for leading researchers in their respective fields to present and discuss scientific research highlights relevant to the utilization of techniques and technologies for studying cell-to-cell communications in cancer. Avenues of future development and the potential for clinical utility were primary features of these discussions. The scientific presentations and extensive ensuing discussions resulted in the identification of a number of research opportunities, which are summarized in this report.

The NIH Extracellular RNA Communication Consortium.

The Extracellular RNA (exRNA) Communication Consortium, funded as an initiative of the NIH Common Fund, represents a consortium of investigators assembled to address the critical issues in the exRNA research arena. The overarching goal is to generate a multi-component community resource for sharing fundamental scientific discoveries, protocols, and innovative tools and technologies. The key initiatives include (a) generating a reference catalogue of exRNAs present in body fluids of normal healthy individuals that would facilitate disease diagnosis and therapies, (b) defining the fundamental principles of exRNA biogenesis, distribution, uptake, and function, as well as development of molecular tools, technologies, and imaging modalities to enable these studies,

Mechanisms of tumor metastasis to the bone: challenges and opportunities.

In human cancers, bone is a common site for metastasis. It is well known that metastasis is the cause of morbidity and mortality in patients with cancer. Both breast and prostate carcinomas have a propensity to metastasize to bone. In general, metastatic breast cancers result in osteolytic lesions. On the other hand, prostate cancer metastases are osteoblastic and result in osteosclerosis. Thus, bone formation and bone resorption are at the crux of the cancer metastasis problem. For example, in the prostate, there is a vicious cycle of metastasis to bone (Fig. 1). Metastases to bone causes excruciating bone pain, pathological fractures, and eventually death, and therefore is a serious challenge to both bone biologists and cancer cell biologists. The stromal-epithelial interactions in breast and prostate are critical in initiation of carcinogenesis and the progression of the metastatic cascade to bone (Fig. 2). Over a hundred years ago, Stephen Paget enunciated the seed and soil hypothesis in which seeds of metastatic cancer cells of breast preferentially settle in the soil of bone matrix. Thus, the prostate/breast cancer bone interface and continuum has continuously presented challenges and opportunities and were discussed at a recent workshop.

Therapeutic targeting of prostate cancer.

An inaugural conference in Tucson Arizona on May 6-9, 2004 brought together more than 70 clinical and basic scientists to discuss recent research advances in understanding and targeting the progression of the human prostate cancer. The informal meeting was unique in that it provided the opportunity for discussion and interaction between these different groups of scientists whose paths rarely cross. The goal of the meeting was to develop new and novel approaches in understanding the human prostate cancer in order to uncover therapeutic targets. Faculty from six different cancer centers were represented including Memorial Sloan-Kettering Cancer Center (New York, NY); Arizona Cancer Center (Tucson, AZ); Fred Hutchinson Cancer Center (Seattle, WA); Chao Family Comprehensive Cancer Center (Irvine, CA); the Sydney Kimmel Cancer Center (San Diego, CA); Jonsson Comprehensive Cancer Center, University of California (Los Angeles, CA); and University of Massachusetts Memorial Cancer Center (Worcester, MA). Several important concepts emerged from this meeting as a result of the basic and clinical science interface. These concepts include: (1) Human prostate cancer has unique biological features as compared to other human epithelial malignancies; (2) Tumor plasticity is evident early in prostate cancer progression as evidenced by alterations in the extracellular matrix; (3) New therapeutic strategies should include the co-targeting of the stroma and prostate cancer; (4) Cell-cell and cell-ECM adhesion switching are reversible phenotypes evident early in human prostate tumor progression; (5) The discovery of molecular signatures including genomic or proteomic patterns for the discrimination of indolent versus aggressive disease is a potentially powerful tool and requires multifactorial approaches for success; and (6) New biomarkers and innovative tissue specific imaging modalities for human prostate cancer are being developed that may aid in a more accurate assessment of prostate cancer in patients.

Vesicle transfer and cell fusion: Emerging concepts of cell-cell communication in the tumor microenvironment.

Cell-cell fusion and vesicle-mediated transfer are fundamental biological processes that are emerging as novel mechanisms for re-programming cells in the tumor microenvironment. Both cell-cell fusion and intercellular transfer of vesicles (including microvesicles and exosomes) allow for the transfer of information among tumor cells, between tumor cells and tumor stroma, and between tumor cells and the host immune system, which could have profound implications for our understanding of tumor initiation and progression. The National Cancer Institute's Division of Cancer Biology sponsored a recent workshop (December 4-6, 2010) entitled, Vesicle Transfer and Cell Fusion: Emerging Concepts of Cell-Cell Communication in the Tumor Microenvironment to assess the current state of the science in these two scientific areas. Co-chaired by Drs. Huang-Ge Zhang (University of Louisville) and Madhav Dhodapkar (Yale University) this workshop brought together, for the first time at the NIH, leaders in the field to assess the effects of vesicle transfer and cell-cell fusion on cancer initiation, progression and metastasis. This meeting report includes brief summaries of the presentations and identifies the major questions, roadblocks, and opportunities. The meeting report is presented here to highlight research priorities and to stimulate basic and translational research efforts to better understand the contributions of cell-cell fusion and vesicle transfer to cancer.