Executive Summary
Introduction
Recommendations

Executive Summary of the Tumor Microenvironment Think Tank

The microenvironment in which a tumor originates plays a critical role in tumor initiation and progression, and may be an important factor in developing therapeutic approaches. The tumor microenvironment, or stroma, influences the growth of the tumor and its ability to progress and metastasize. It also can limit the access of therapeutics to the tumor, alter drug metabolism and contribute to the development of drug resistance. Because of their role in all the stages of tumor development, stromal elements represent attractive therapeutic targets. Manipulating host-tumor interactions may be important in preventing or reverting malignant conversion, and re-establishing normal control mechanisms.

Despite the importance of tumor-stromal interactions, there is a limited understanding of the stromal composition, and of the complex relationship between the tumor cells and the surrounding host cells. It is now acknowledged that tumor cells and their stroma co-evolve during tumorigenesis and progression. Stroma consists of cells, extracellular matrix and extracellular molecules. Among the identified cells are fibroblasts, glial cells, epithelial cells, adipocytes, inflammatory cells, immunocytes, and vascular cells. However, the precise nature of the cells that comprise normal stroma, how these cells or newly recruited cells are altered during tumor progression, and how they reciprocally influence tumor initiation and progression are poorly understood.

As these salient and outstanding questions are addressed, it will be possible to begin to develop complementary therapeutic strategies targeted at both the microenvironment and the tumor. Among the approaches envisioned to target the tumor microenvironment are the development of drugs that induce apoptosis or inhibit the function of the stromal cells, or the factors secreted by stroma that are required for tumor progression and metastasis. It is expected that understanding the tumor microenvironment will lead to the development of better diagnostic tests and/or improved therapeutic strategies. Finally, it may be possible to develop strategies to prevent the development of tumors based on our understanding of alterations in the microenvironment that enable tumor development.

The research priorities listed by the think tank include: a better understanding of tumor microenvironment, and the identification and characterization of the signatures of seemingly normal cells within the tumor microenvironment and signatures that reflect changes that occur as cancer cells interact with the host microenvironment. Achieving these goals can be expedited by encouraging interdisciplinary research teams and multi-institutional collaborations. Similarly, advances in technologies will be critical for progress. Among the technologies that have been identified as critical are: 1) novel in vitro 3D matrix reconstitution and organotypic models, and animal models; 2) techniques, such as laser capture microscopy, for the isolation and characterization of stromal cells; 3) the discovery of novel stromal markers through molecular profiling and their application for the development of reagents for in vivo imaging to visualize tumor-host interactions. These technologies will provide the tools for a better understanding of the tumor microenvironment and for the development of tissue- or cell-specific targeting agents. Successful approaches to respond these needs can have a dramatic effect on making the tumor microenvironment "hostile to the tumor," thereby transforming cancer into a "chronic, but benign" disease.

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Introduction

The intrinsic and extrinsic influences that transform a normal epithelial cell into a malignant cell are very complex. Enormous advances have been made over the last several decades in identifying the molecular and genetic changes of cancer cells and the pathogenesis of neoplasia. This has led to the identification of oncogenes and tumor suppressor genes and associated signaling mechanisms by which they modulate growth, survival and proliferation. These studies have generated novel therapeutic reagents such as Tamoxifen, Herceptin and Gleevec.

Stromal influence on epithelia cells begins at fertilization and continues during adulthood, wherein the microenvironment controls normal development and homeostasis. For example, macrophage association with the developing mammary gland is critical during development and CSF-1 or CSF-1R null mice (devoid of macrophage) have defective mammary glands.

Research on tumor-host interactions collectively suggests that (a) tumors are not autonomous masses of cells but function as organs composed of many interdependent cell types that contribute to tumor development and metastasis, and (b) the interactions between the tumors, the extracellular matrix (ECM) and stromal cells is bidirectional and dynamic; stromal cells include fibroblasts, adipocytes, glial cells, smooth muscle cells, and resident and recruited vascular and immune cells.

The tumor microenvironment and the malignant cells themselves constitute the tumor entity that clinicians confront when treating cancer patients. The cell-cell and cell-matrix interactions that influence the behavior of cancer cells are targets with as much potential for the development of effective therapies as the tumor cells themselves. The microenvironment can exert both positive and negative influences on tumor cells. Stromal cells can also impart stimulatory and growth inhibitory effects on tumor cells, e.g., the malignant potential of teratocarcinoma cells can be restrained during embryonic development resulting in cancer-free adult mice. Similarly, attenuation of β1 integrin (laminin receptor), EGFR or MAPK activation in highly aggressive human breast cancer cells results in a reversion of the aggressive phenotype.

The cancer cell is absolutely dependent on the stroma for its proliferation, progression, and metastasis; examples include the role of inflammatory cells (via cytokine and protease secretion) in tumor cell proliferation, angiogenesis, invasion and metastasis; the interaction of host immune cells with the vasculature; the interaction of tumor cells with the angiogenic endothelial cells, and the role of lymphangiogenesis during metastasis to the regional lymph nodes. Stromal cells can also influence organ-specific metastasis as evidenced by the role of stromal-derived cytokines and growth factors (e.g., PTHrP, CXCR4, SDF1, TGF B and RANKL) in breast and prostate cancer and multiple myeloma metastasis to bone. Finally, interaction of bone marrow stromal cells with multiple myeloma cells has been shown to contribute to the development of drug resistance.

Stroma can be targeted for therapy. Recent successes (a) in patients with multiple myeloma, where bone marrow stroma was targeted using proteasome inhibitor to attenuate bone metastasis, and (b) the development of anti-angiogenic drugs (Avastin and Thalidomide) which target the endothelial cells illustrate progress towards this goal.

The two major goals are: to obtain information about the microenvironment that would facilitate the diagnosis, prevention or treatment of cancer, and translating this information into useful clinical applications. These broad goals can be achieved through the following specific objectives: (1) identify the key components of the tumor microenvironment and define how these are altered during tumor development. Identify the stromal compartment of normal tissues and compare how these are altered in carcinogenesis. (2) Determine which alterations in the tumor microenvironment that are critical for the development, progression and metastasis; elucidate the mechanism responsible for induction of these changes. (3) Identify tumor cell stem cells and characterize the interactions between stromal cells and tumor stem cells, as well as the role of tumor stem cells in metastasis. (4) Develop therapeutic strategies to target the tumor microenvironment and interfere with site-specific metastasis by the (a) development of drugs that induce death or inhibit the function of the stromal cells that are required for progression; (b) development of reagents to target specific factors produced by stromal cells that are responsible for progression, and (c) blocking the induction of stromal factors responsible for tumor cell survival and proliferation. (5) Develop diagnostic tests to predict outcome and/or design treatment. (6) Develop strategies to prevent the development of tumors based on an understanding of the alterations in the microenvironment essential for tumor development.

These issues can be best addressed with the availability of novel technologies and model systems. Thus the development of novel in vitro 3-dimensional matrix reconstitution and organotypic models or animal models, isolation of stromal cells from normal and tumor cells using techniques such as Laser Capture Microdissection will aid in the identification of stromal markers through molecular profiling technologies. The availability of stromal markers will facilitate better reagent development for in vivo imaging to visualize tumor-host interactions as tumor cells invade and metastasize. The availability of stromal markers will also expedite the generation of reagents for tissue- or cell-specific targeting.

Significance

Critical stromal elements of the tumor are attractive targets for prevention, because they have maximal influence over tumor cells in the early stages of tumor development. As targets for therapy, they are less likely to be genetically unstable than tumor cells and thus less likely to develop drug resistance. Manipulating host-tumor interactions has the potential of reverting the malignant phenotype and establishing normal control mechanisms. Eventually, the desired goal is to reduce or eliminate metastasis-associated morbidity and transform cancer metastasis in to a chronic but benign disease.

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Specific Recommendations for the NCI

1. Establish an Interdisciplinary Tumor Microenvironment Network that includes pathologists, cancer biologists, cell biologists, oncologists, engineers, physicists, bioinformatics experts and industry representatives. Such a group will facilitate the study of normal and malignant tissue microenvironments. This can be accomplished by both centralized resources and widespread, varied funding opportunities.

2. Encourage study of the normal tissue microenvironment as a prerequisite for understanding the microenvironments of wounded tissues and tumor tissues

Establish and support a repository of normal stromal cells and matrix molecules to facilitate this research

Develop additional and improved 3-dimensional reconstitution and organotypic models that will permit the in vitro study of microenvironmental elements

Key issues in understanding normal stroma are

• What % of tumor is stroma?


• What are the various cells in the stroma?


• What are the matrix molecules?


• How does it change over time and with tumor progression?


• Genomic and proteomic analysis of tumor stroma and involvement of bioinformaticists

3. Develop a better understanding of tumor dependence on stroma

• Since experimental manipulation of stromal components in vivo has profound effects on tumor growth, progression to metastasis and immune response, there is a need for selective agents that target specific cellular and molecular stromal elements, and inhibit tumor progression.

4. Delineate the role of the microenvironment in tumor progression – key issues

• Do tumor promoters affect the stroma and facilitate metastasis?


• Are there differences between the microenvironment of a primary tumor as compared to secondary sites?


• Does the stromal compartment contribute to the "metastatic signature" of tumors?


• Are some 'stromal' cells really tumor cells in disguise?


• Can the microenvironment of tumors be effectively neutralized to inhibit progression?


• Is organ metastasis achieved solely via hematogenous spread, or do transiting cells initially exit via lymphatics and subsequently spread hematogenously?


• What is the role of inflammatory cells during invasion, migration, tumor growth and metastasis? To achieve this it will be necessary to study inflammation in vivo, in relevant immune-competent (mouse) models of progression (transgenic or syngeneic xenograft).


• Do stromal elements interact or modulate the tumor stem cell 'niche' and do these interactions change as tumor progress and metastasize?

5. Stromal Genetics – key issues

• What is the role of host genetics in influencing the stromal formation?
• Does stromal composition differ in different inbred mouse strains?
• Do epigenetic changes influence stromal composition?

6. Encourage the use of existing technologies for visualizing the components of the stroma at the level of individual cells and molecules

• Expand access to multiphoton microscopy and deconvolution microscopy to study the microenvironment.


• Develop novel imaging technologies to study tumor microenvironment; recruit/collaborate with engineers and physicists who can apply the most current imaging technologies to the study of the normal and tumor microenvironment.

7. Translation of basic knowledge to human disease

• Discover and validate therapeutic targets derived from the tumor microenvironment


• Encourage mouse and human research to improve our chances of discovering useful targets.

8. Role of NCI

• Establish a network of interconnected, multidisciplinary investigators and collaborative groups to work together on understanding the tumor microenvironment, facilitated by both centralized resources and widespread, varied funding opportunities.

Such an infrastructure should

• Provide centralized administrative support


• Provide and maintain repositories


• Produce and distribute reagents


• Provide core facilities


• Facilitate interdisciplinary collaborations


• Train scientists

• Animal models / fluorescent markers


• Imaging (multiphoton) at one micron resolution


• Spectral deconvolution microscopy


• Selection of live cells from tumors


• 3D matrix reconstitution


• Organotypic models

• In individual labs


• In "Centers of Excellence"


• In central or decentralized cores


• At meetings and conferences


• At courses on the tumor microenvironment

9. Establish and encourage a Systems approach to the study of the tumor microenvironment

10. Encourage interactions with other NCI-supported multidisciplinary groups such as EDRN, MMHCC, SPOREs, and Cooperative Groups

11. Encourage interactions with other ICs with similar interests (NIEHS, NIDDK, NHLBI, NIAMD, and NIDCR)

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