Current Cancer Drug Targets - Volume 8, Issue 6, 2008

Many of the currently available anti-cancer therapeutics are based on the concept of targeting tumor cells. However, the tumor stroma has also become a major focus of attention as a therapeutic target. An early attempt to target stromal components, in the 1990s, involved the matrix metalloproteinases (MMPs), that can be expressed by various cell types in the tumor stroma. MMPs were targeted in human cancer with synthetic inhibitors, however, these compounds failed in clinical trials, in part because the complex mechanisms-of-action of MMPs, and the biology of the tumor stroma, were not well understood. Typically, the tumor stroma can consist of extracellular matrix as well as a range of cell types, including fibroblasts, the endothelial cells of blood vessels and lymphatic vessels, and immune cells such as monocytes and macrophages. The cells of the tumor stroma can be important for sustaining or promoting the growth and metastatic spread of solid tumors. For example, tumor angiogenesis, that gives rise to tumor blood vessels, promotes tumor growth and presumably facilitates metastatic spread via the bloodstream. Moreover, tumor lymphangiogenesis, that increases the abundance and possibly the size of peritumoral or intratumoral lymphatics, may facilitate metastatic spread of tumor cells to regional lymph nodes and possibly to more distant sites in the body. Recent studies have indicated that components of inflammatory infiltrate in solid tumors, particularly macrophages, can play a role in recruiting blood vessels thereby facilitating tumor growth. The communication between tumor cells and stromal components is facilitated by a range of growth factors, growth factor receptors and proteases. Members of the VEGF family of glycoproteins are important for recruitment of tumor blood vessels and lymphatics, Wnt signaling pathways are involved in signaling between epithelial cells and stromal cells, TGF-β is thought to play a role in the tumor-promoting activities of cancer-associated fibroblasts, and the Eph receptors and their ephrin ligands may be important for migration of stromal cells associated with tumors. Each of these signaling systems is examined by an article in this issue. The growth factors and receptors that are essential for such signaling pathways are potential therapeutic targets in cancer - some, including VEGF-A and VEGF receptors, have already been exploited for development of anti-cancer therapeutics. The emerging technologies of “systems biology” will surely prove useful for defining the circuitry of biological signal transduction pathways that control the interaction of tumor cells with components of the tumor stroma. This information will be essential for understanding how distinct signaling pathways can influence each other to determine outcomes in terms of tumor biology. The targeting of the tumor stroma will undoubtedly become a more prominent theme for anti-cancer therapeutics in future. We trust that this issue, which explores i) the biology of the tumor stroma, ii) specific signaling pathways involved in communication between tumor cells and stromal components, and iii) therapeutic strategies for targeting stromal components, will provide a useful overview of current activities in this rapidly developing area.

Solid tumors are composed of the malignant cell itself (most commonly a carcinoma) and supporting cells that comprise the stroma. Significant stromal components include the extracellular matrix, supporting fibroblasts, vessels comprised of endothelium, pericytes and in some cases vascular smooth muscle, lymphatics and usually a major leukocyte infiltration. Indeed, macrophages may constitute up to 50% of the viable cells within the tumor. For many years, researchers have concentrated almost exclusively on the malignant carcinoma and looked for ways to either selectively kill or restrict its growth. In recent years the frustrating lack of advances in cytotoxic cancer therapy provoked a search for more novel strategies and foremost amongst these were anti-angiogenesis and vascular targeting. The purpose of this article is to illustrate how the stroma is now being pursued as an anti-cancer target. The article will briefly touch on antiangiogenics that are now entering the clinic but concentrate on recent studies looking at vascular disrupting agents, stromal tumor fibroblasts and macrophages. Target identification is illustrated by the search for tumor endothelial markers. Finally, we draw attention to efforts to develop a cancer vaccine. The genetic instability and variation found in carcinoma cells made vaccination in the past a near impossibility. In contrast, genetically stable tumor endothelium with its unique accessibility to blood borne agents, together with recent advances in immunotherapy means that the possibility of a cancer vaccine now takes on a reality not previously recognised.

Wnt signaling plays an important role in cancer. Signaling is initiated by binding of Wnt ligands to Frizzled cell surface receptors and results in signaling via one of three pathways, the canonical Wnt pathway, which is the best characterized in both normal tissues and in cancer, and two non-canonical Wnt pathways, the Ca2+-dependent and the PCP pathways. Canonical Wnt signaling results in β-catenin accumulation in the cytoplasm, translocation into the nucleus and activation of transcription of Wnt target genes including the c-Myc oncogene. Some cancer types, including colorectal cancer, have mutations in APC and Axin, which are involved in β-catenin phosphorylation, such that the canonical pathway is constitutively active. Few studies have investigated the role non-canonical Wnt signaling in cancer, or of Wnt signaling on tumor stromal cells. Wnt overexpression is observed in tumor stroma, as is overexpression of the Wnt pathway inhibitors, secreted Frizzled-related proteins and Dickkopf proteins. Interactions between epithelial cells and stromal cells have been observed to activate Wnt signaling in both cell types. Wnt signaling is also observed in tumor blood vessels and is likely to be activated by signals from tumor cells. Current cancer therapies focus on interfering with canonical Wnt signaling in the tumor cells. Future therapeutic targets for interfering with Wnt signaling include cell surface receptors such as the RYK and Ror2 receptors and secreted signaling molecules, which mediate signaling between cancer cells and the stromal environment.

Recent findings have demonstrated that the tumor stroma actively contributes to tumorigenesis. The communication of malignant cells and tumor stromal components is orchestrated in part by a network of growth factors. One of these growth factors is transforming growth factor-β (TGF-β), a secreted multifunctional protein that acts in a highly cellular contextual manner. TGF-β can either stimulate or inhibit the tumor-promoting effects of the different components of the tumor stroma. In this review, we discuss our current understanding on how TGF-β influences different stromal compartments.

Eph receptors and their membrane-bound ephrin ligands are developmental cell guidance cues that direct cell migration and orchestrate patterning processes by modulating adhesive or repulsive cell properties. During the past two decades, an exponentially growing interest in their function has resulted in a considerably advanced understanding of the cellular and molecular principles of Eph function in normal and oncogenic development. Ephs not only accurately guide the path of migrating cells, but also facilitate contact and communication between neighbouring cell populations, in particular at epithelial/mesenchymal boundaries. Precise cell positioning not only relies on accurately-graded expression of individual Eph/ephrin pairs, but on the sum of interactions within particular expression domains and their modulation through crosstalk with a range of other signalling systems. There is little doubt that Eph and ephrins provide exciting new targets for anti-cancer therapies, but in appreciation of the complexity of their signals and biological functions it is perhaps not surprising that the development of Eph-specific therapeutics is only emerging.

Although it is evident that prostatic epithelial stem cells are responsible for maintaining normal and malignant tissues, it is well recognized that epithelial cells do not exist independently, but act in concert with the stromal microenvironment. Prostatic stroma is pivotal for normal development and homeostasis. The genetic and morphological changes that occur in prostatic epithelial cells, as they progress from a normal to malignant phenotype, have been well described. However, it is evident that the surrounding microenvironment also plays a major role in cancer cell growth, survival, invasion and metastatic progression. Prostatic tumor stroma provides a niche environment for cancer stem cells and therefore contributes to self-renewal and differentiation. In order to target the tumor microenvironment and develop new therapeutics for prostate cancer, we must understand the role of the tumor stroma, specifically the events mediating the interactions between the cancer stem cell and its immediate microenvironment during cancer initiation and progression. This article presents the rationale and discusses the challenges to targeting prostatic tumor stroma in cancer therapies that will potentially treat prostate cancer.

Many recent advances in cancer therapy have been based on an understanding of the basic biology of the cancer cell itself, particularly with respect to abnormalities in various signalling pathways. It has become increasingly apparent that malignant cells exist in a complex cellular and extracellular microenvironment, which can play key roles in the initiation and maintenance of the malignant phenotype. These interactions can provide therapeutic targets that are now being exploited in the clinic. Much attention has been paid to agents that disrupt angiogenesis or existing tumor vasculature, however other cellular and non-cellular components of the tumor mass mediate critical functions and can also be useful treatment targets. Treatments directed at these interactions bring new challenges in terms of how best to develop these strategies, and require approaches that differ in many ways from conventional anticancer therapies.

Squamous cell carcinoma of the esophagus is one of the ten most frequent malignancies worldwide, characterized by a striking geographic variation in incidence. In North America and Europe, there has recently been a marked change in the epidemiology of this disease, where incidence rates for primary esophageal adenocarcinoma have increased in excess of any other human solid tumor. Although the reasons for this are largely unknown, several molecular genetic alterations have been associated with esophageal tumor progression. In recent years, epigenetic aberrations have been increasingly recognized as an important alternative mechanism of carcinogenesis and it is anticipated that substantial progress in the treatment of esophageal malignancy will likely only be made with a clearer understanding of esophageal tumor biology. Whereas genetic mutations, deletions, or allelic losses are fixed and irreversible, epigenetic abnormalities can potentially be corrected without interfering with the fundamental sequence of the target gene. Our current understanding of epigenetics in esophageal cancer, and the potential for targeted epigenetic therapy, will be the subject of this review.

Hsp90 (heat shock protein 90) is a molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory, metabolism, organization, and signaling proteins. Binding to Hsp90 is required for normal function of many proteins. In addition, Hsp90 has an extra-cellular function. It is found in two isotypes: α which is inducible and β which is constitutive. Tumor cells frequently over express Hsp90α, and Hsp90 is implicated in cancer progression. Hence Hsp90 has emerged as a potential target for cancer treatment. A variety of agents have been found to interfere with Hsp function, mainly by binding to an ATP binding site on the molecule. More recent agents interfere with protein binding or the dimerization of Hsp90 needed for function. Preclinical studies have demonstrated that disruption of the many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. As a result, agents which interfere with this protein's function are being tested in the clinic as a targeted method of interfering with malignant growth. We review the current clinical status of therapeutic efforts to perturb this pathway and discuss future directions.

Resistance of human cancers to current treatment approaches remains a challenge in oncology. Therefore, there has been much interest in identifying molecular pathways that are responsible for primary or acquired resistance of cancers. Since most anticancer therapies, i.e. chemotherapy or radiotherapy, primarily act by triggering programmed cell death (apoptosis) in cancer cells, defects in apoptosis programs may confer resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by the dominance of cell survival pathways, for example aberrant activation of the PI3K/Akt/mTOR cascade, or alternatively, by defective expression or function of critical mediators of apoptosis, i.e. components of the TRAIL signaling system. In addition, signaling to apoptosis can be blocked under hypoxia, a characteristic feature of most solid tumors including rhabdomyosarcoma that has been associated with poor treatment response. Thus, molecular targeted therapies that are specifically directed to the defects in apoptosis programs, open novel perspectives to restore apoptosis sensitivity in rhabdomyosarcoma.