There is growing evidence that the relationship between the inflammatory process and cancer is complex. Our understanding of this relationship as it relates to both development and progression of malignancy is still limited. Further evaluation in human subjects is clearly needed if we are to truly understand whether there is therapeutic potential in targeting inflammation, or the consequences of inflammation, as an approach to treating established cancer. Several important steps need to be taken before we can know the true potential of such an approach to cancer therapy. The lack of standard nomenclature with respect to describing and grading the extent and type of inflammation within a tumor sample limits our ability to compare results from one study to another. The development of such standard criteria, as are in use for other pathologic processes, would provide consistent and accepted approaches to evaluating the number, type, and location of various inflammatory cells. Such criteria will no doubt evolve over time, and may vary from tumor type to tumor type, as data emerges relating to the clinical significance of different types and degrees of inflammation within a tumor. Nevertheless, the time is right to establish a first generation of standard criteria for describing and grading inflammation within tumors.
At this point, it is difficult to know in a particular scenario whether inflammation within an established tumor is “friend or foe”. We do not know whether inflammation is enhancing tumor-growth or providing a receptive environment for metastasis, or is serving to inhibit tumor progression. Before agents specifically designed to target inflammation within a tumor are evaluated clinically, it will be important for such basic questions to be understood. It is highly likely that the impact of inflammation will vary based on a number of factors. For example, inflammation could have a significantly different effect on the primary tumor vs metastatic disease. There are also likely to be differences in the impact of inflammation on cancer progression when comparing untreated tumors vs those being treated with traditional cytotoxic agents. That inflammation plays different roles early in oncogenesis (promoting) and later in progression (antitumor) is supported in several systems: for example, pro-inflammatory cytokine levels in patients before treatment predict the benefit of IFN immunotherapy (144
). An additional issue deserving of further study will be the impact of inflammation on cancer vaccination strategies, both at the site of immunization and at the site of the effector immune response, in the tumor, and perhaps the draining lymph nodes.
Animal models have taught us much about tumor biology and identification of targets for tumor therapy. They also provide important information on mechanism of action of therapeutic agents. However, there are significant limitations to using animal models as tools to refine approaches to cancer therapy. Investigators often optimize the animal model to fit the therapy under evaluation, as opposed to optimizing the therapy to fit the animal model. This may enhance our ability to cure animals but does little to provide evidence of the likelihood of successful clinical development of the agent. Mouse models most often involve inbred animals and implanted tumors which lack not only the tumor heterogeneity but the heterogeneity of the host immune system that can have a significant impact on the inflammatory response within the tumor. Investigators prefer models where the tumor grows rapidly, thereby allowing experiments to be done relatively quickly. Such rapidly growing tumors are obviously very different from human tumors that often develop, over many years, from premalignant lesions, grow more slowly, and have more extensive interactions with non-malignant cells within the tumor mass including inflammatory cells. Thus, while animal models are extremely useful for understanding biology and mechanisms of action of therapeutic agents, they are of limited use in fine-tuning the treatment or predicting the likelihood of clinical success of a given treatment approach. This is particularly true for therapeutic strategies targeting inflammation within tumors where the behavior of the malignant cells, and the host immune system, and how they interact, are of critical importance.
Given our limited understanding of the potential of inflammation within tumors as a target for therapy, a focus on clinical correlative studies, as opposed to design of clinical studies specifically geared towards inflammation, is likely to be most informative. Unfortunately, opportunities continue to be lost when clinical trials geared toward development of new biological therapies focus solely on clinical response rates and toxicity, with little attention played to the mechanisms and biologic changes induced by the therapeutic approach. A number of agents that would be expected to have a significant effect on inflammation within tumors are FDA approved (e.g. Bortezumib, Cytoxan and glucocorticoids) or under various stages of clinical development, yet we know little about the effect these treatments have on inflammation within tumors. Having such information would be valuable in designing subsequent studies. The hesitancy of many pharmaceutical and biotechnology companies to support correlative laboratory studies geared towards understanding mechanisms of action needs to be overcome if we are to develop strategies based on new areas of therapeutic potential such as targeting inflammatory responses in tumors. Although the timing can be challenging, correlative laboratory studies can sometimes be supplemented by non-commercial approaches to funding through the government or other sources of cancer research funding. Rigorous, well-designed smaller studies that involve sample collection, clinical evaluation, and extensive followup may well be more valuable (and certainly more practical) in this regard than the larger, multicenter, comprehensive clinical trials, especially since such larger studies often fail to collect the kind of data needed to address these questions.
Multiple factors in both the host and the malignant cells are likely to affect the impact that the malignancy has on the inflammatory response, and the impact that the inflammatory response has on the malignancy. Understanding these factors, and their relationship to treatment response, would be a central goal of correlative studies. For example, within the host, there is clearly heterogeneity in the immune response that can be evaluated genetically through the study of single nucleotide polymorphisms in immune response genes, and environmental factors such as ongoing infection that might provide ongoing signals, such as through TLRs, that impact on the inflammatory response. Within the malignant cells, signaling pathways, and production of cytokines or expression of receptors clearly play a role in how host inflammatory cells impact on the malignant cells and need to be evaluated. For example, increasing data indicates STAT 3 and STAT 5 are important in head and neck squamous cancer, prostatic adenocarcinoma, and melanoma. Understanding the effects of immunotherapy such as IFNα has on the abrogation of the immunosuppressive and anti-inflammatory effects of constitutive STAT3 activation will be very helpful in expanding our understanding why such agents mediate, or fail to mediate, an anti-tumor response. It is simply too early in our understanding of these relationships to rationally design therapeutic approaches geared specifically towards modifying these interactions in a way that will have a positive clinical impact.
Another important question related to the role of inflammation in cancer involves use of newer imaging techniques to assess response to therapy. Techniques such as position emission tomography measure cellular activity. Inflammatory cells are highly active metabolically and so can impact on our ability to correlate clinical functional imaging results with malignant activity within a tumor mass.