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.

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,

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.

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.

The biology of hormone refractory breast and prostate cancer: An NCI workshop report.

The molecular regulation of growth and progression of hormone refractory breast and prostate cancers remains challenging. The Division of Cancer Biology, NCI organized a small "think tank" style workshop and invited scientists in relevant areas to assess the state of science on the biology of hormone refractory tumors and to identify potential research opportunities to enhance a better understanding of the molecular regulation of these tumors. The meeting, held on May 27-29, 2008 in Bethesda, MD, was co-chaired by Drs. Michael Geoffrey Rosenfeld and Michael Press. While expression of estrogen or progesterone receptors (ER/PR) is required for benefit from endocrine manipulations, many women with breast cancer will not respond to primary endocrine manipulations despite ER/PR expression, and others acquire resistance while on treatment. Understanding the mechanisms that lead to Hormone Refractory Breast Cancer (HRBC) and defining interventions that may modulate the resistance to endocrine therapy are currently lacking. In contrast to breast cancers, the vast majority of both early and advanced prostate carcinomas exhibit androgen-pathway activity at diagnosis and the vast majority respond to treatments designed to inhibit AR-signaling. However, after initial benefit, advanced prostate cancers regularly progress to a clinical state termed Castration Resistant Prostate Cancer (CRPC) that reflects a diverse array of molecular events maintaining AR signaling. The workshop focused on both common and unique features of hormone refractory breast and prostate cancer with an orientation toward defining major research questions, delineating opportunities and recommending strategies for overcoming barriers to progress in understanding these important clinical disease states.

Tumor cell dormancy: an NCI workshop report.

The long latency period that occurs in some patients between initial treatment and evidence of metastases is attributed to tumor cell dormancy. Although the clinical occurrence of these late developing metastases has intrigued the medical community for years, there's a paucity of experimental data, especially among the solid tumors. Of clinical importance is that dormant tumor cells are highly refractory to chemotherapy. For these reasons, the NIH convened a small workshop in July 2006 of investigators with interests in this field to review the challenges and research opportunities. This report summarizes the key outcomes of this workshop. The mechanisms associated with tumor cell dormancy are poorly defined, in part because the dormant tumor cells have been extraordinarily difficult to isolate. New isolation and characterization techniques were presented. One of the critical limitations confronting the field is that molecular markers of dormancy are not now known. The workshop considered the role of the microenvironment in promoting and maintaining dormant tumor cells as well as events in the microenvironment that could activate the dormant cells. There was also discussion of new models of dormancy and new imaging modalities. Furthermore, the workshop reviewed studies of hematological tumor cell dormancy and how this insight could best be applied to the solid tumors. Finally, there was discussion related to the design of clinical trials for the study of tumor cell dormancy. The workshop concluded with an overall summary of the challenges and research opportunities associated with this field with recommendations for consideration by the NIH.

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.

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.

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.

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.