Radiotherapy (RT) regimes used to treat approximately 50% of cancer patients each year in the USA and Europe are curative in several diseases and substantially increase tumor-free survival in many others. The physical attributes of ionizing radiation (IR) provide therapeutic focus on the cancer itself and, in conjunction with sophisticated treatment planning and technological innovations, limit toxicity in non-tumor tissue. In contrast to current empirical testing of combination therapies, future innovation will be predicated on understanding the complex biology elicited by radiation as a function of tissue, dose, and individual susceptibility. A new wave of radiobiology is evolving that refines the target of systemic therapies to the specific biology induced by radiation.
The microenvironment is a particular focal point of this strategy with the growing appreciation that irradiation induces specific and persistent changes in signaling that are mediated via the microenvironment interface. In the most comprehensive definition, microenvironment is comprised of soluble signals like cytokines, growth factors and reactive oxygen species, insoluble extracellular matrix and cell types other than the tumor cell. The microenvironment of each organ and tissue develops to specifically support the function of those cells, while tumor microenvironments are subverted to promote tumor growth and expansion at the expense of normal tissue. Radiation therapy changes both, frequently in a manner that is reminiscent of processes associated with wound healing or inflammation. Defining the nature of the irradiated microenvironment provides a means of further targeting therapies directed towards inhibiting normal tissue toxicity or improving tumor control.
The workshop on ‘Radiation and Multidrug Resistance Mediated via the Tumor Microenvironment’, held in Dresden from 12 – 13 February 2007, provides a glimpse of novel strategies that combine targeted radiotherapy with systemic pharmaceuticals that preferentially affect the responses of irradiated cells. Three major signaling pathways were highlighted: transforming growth factor β (TGFβ), integrins, and epidermal growth factor receptor (EGFR).
EGFR is perhaps the most mature since agents against EGFR are already in use for treating certain cancers, e.g. lung cancer. The rationale for their combination with RT is well advanced. Studies presented by Baumann and colleagues have providing compelling evidence that anti-EGFR strategies using humanized antibodies (C225) are associated with radiocurability in murine tumors, possibly by diminishing tumor cell repopulation. Farnylstransferase inhibitors that target Ras downstream of EGFR have potential clinical applications as described by McKenna and colleagues. In combination with RT increased radiosensitivity and tumor control are accompanied by decreased hypoxia, suggesting additional vasculature targets. Since IR induces EGFR pathway activation via ligand independent and dependent routes, there is potential advantage in combination with fractionated radiation. Consistent with this approach, Rodemann and colleagues (Rodemann et al., this issue) have proposed an intriguing dual mechanism in which blocking EGFR increases radiation sensitivity by inhibiting DNA protein kinase catalytic subunit (DNA-PKcs) by affecting classic signaling via protein kinase B (PKB/AKT) in parallel with a route via Caveolin-1 mediated receptor internalization leading to direct interaction with DNA-PK in the nucleus.
Indeed there is increasing evidence that growth factor signaling may be more closely networked with the DNA damage response than previously thought. Barcellos-Hoff reviewed recent publications that TGFβ functionally intersects with the DNA damage pathway via an unexpected requirement in ataxia telangiectasia mutated (ATM) kinase activation. While IR induces rapid and persistent TGFβ activation, blocking TGFβ before IR inhibits ATM kinase activation in epithelial cells and increases cell kill. In conjunction with contributions to radiation-induced fibrosis, these data suggest that there may considerable advantage to the application of TGFβ inhibitors in RT (Andarawewa et al., this issue).
Integrin signaling links the tumor cell to the microenvironment and is instrumental in malignant behaviors like survival, proliferation, invasion and motility. Park proposes that β1 integrin, which is radiation-induced and frequently overexpressed in breast cancer, provides a target for increasing radiosensitivity. She has used tumor cells embedded in extracellular matrix material and in vivo xenografts to elicit cell-cell interactions that are targeted by β1 integrin blocking antibodies (Cordes & Park, this issue). Furthermore, Cordes and colleagues demonstrated that the integrin associated adapter protein lin-1, isl-1, mec-3 (LIM)-only and a particularly interesting new cysteine-histidine rich protein-1 (PINCH-1) affects the cellular radiosensitivity of human lung cancer cells. This enhancement of radiosensitivity seems to be due to modification of Akt function and activity by PINCH-1 as observed in two- as well as in three-dimensional cell culture models (Sandfort et al., this issue). In further support of the well known phenomenon termed cell adhesion-mediated chemoresistance, Sethi summarized the latest findings on how the extracellular matrix protects small cell lung cancer cells against chemotherapy-induced cell death and apoptosis (Hodkinson et al., this issue). With regard to integrins and cancer, Danen and colleagues presented new findings that reveal a regulatory function of αvβ3 integrin in oncogenic c-Src signaling (Huveneers et al., this issue). Being specific for binding cells to laminins, integrin α6 was the focus of work from Cress and colleagues demonstrating that specific cleavage of this integrin sensitizes human prostate carcinoma cells to IR (Pawar et al., this issue).
Beyond intrinsic pathways that mediate tumor cell radiosensitivity, tumor microenvironments modulate host defenses. Focusing on cell interactions beyond the tumor, Wright showed evidence that the host genotype affects the response of macrophages to radiation, which in turn modifies the tissue microenviroment leading to delayed genomic instability (Wright, this issue). Formenti discussed data that suggests how RT can play a significant role in activating immunological mechanisms that suppress tumor growth (Demaria & Formenti, this issue). The particulars of tumor physiology have provided insight for the regulation of critical variables like oxygen. Pouysseguer discussed the regulation of hypoxia induced factor 1α (HIF-1α) by oxygen sensor mediated degradation and the consequences to tumor phenotype via activation of other transcriptional pathways. Likewise, Muschel focused on the physiological determinants of protease activity in tumors and their contribution to vascular integrity. Therapeutic targeting of non-tumor cells is perhaps one of the most promising areas of discovery. Recent evidence is that radiation and anti-angiogenic therapies can have unexpected beneficial interactions during RT. Since angiogenesis and proteases are critical for cell migration and invasion, Friedl highlighted these two mechanisms by presenting time-lapse microscopy. Intriguingly, cells switch from an integrin/protease-dependent migration process to an integrin/protease-independent one under inhibition of integrins and/or proteases. Thus, the exploitation of the complexity of the tumor microenvironment can only be realized by using models that incorporate multiple cellular constituents and understanding the signaling between them.
Additional aspects discussed at this workshop (and summarized in mini-reviews in this issue) were specific integrin-associated proteins such as integrin-linked kinase (Hehlgans et al., this issue) and Caveolin-1 (Shatz & Liscovitch, this issue), EGFR and cell adhesion (Eke et al., this issue), the tumor microenvironment and the immune system (Krause et al., this issue), tumor-stroma interactions (Lacina et al., this issue; Friedrich et al., this issue) as well as low dose radiation (Bauer, this issue) and heavy ion radiation (Götze et al., this issue).
There is clear benefit to focusing on tumor radiobiology in terms of therapeutic targets that are induced by RT: By taking advantage of the biology following targeted radiation, rationale chemotherapy regimes could gain from an enhanced differential between tumor and normal tissue. The use of radiation biology to sharply focus chemotherapy and the design of new targeted drugs has significant potential for improving combined modality therapy.