Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma
Source: Molecular Cancer Therapeutics
In mesothelioma research, as in most forms of disease research, the attempt to understand the basic biological features of tumor growth is one of the most active areas of contemporary study. Investigations in this area continue for nearly all forms of cancer with the ultimate goal being the development of therapeutic tools and strategies that allow doctors to precisely target the particular tumor-types involved with an individual’s cancer. If they can develop modalities that target the particular biological processes involved in tumor genesis and progression, they may be able to develop treatment tools that demonstrate both greater therapeutic efficacy and reduced side effects.
In the case of mesothelioma, this category of research has had scientists studying the relationship between a wide variety of tumor structures, malignant and non-malignant cell types and host-induced co-factors for insight into better treatments for mesothelioma. One of the most compelling of the recent research hypotheses has to do with the role that macrophages play in cancer growth. Previous studies have noted some correlation between macrophage density and tumor burden—especially with epithelial cancers, where 80% of the studied cancers demonstrated a correlation between greater macrophage density, tumor stage and poor prognosis. In recognition of those findings, an international team of researchers endeavored to study this relationship further. Their recently-released results do note a significant relationship between a certain type of macrophage and tumor growth and this article is a summary of the findings as presented in their paper.
Overview of the Study
Macrophages are an important type of immune system cell. They are normally responsible for the removal of foreign antigens and invading organisms through a process known as phagocytosis, where they engulf and essentially digest the antigen. They originate from monocytes(one of the immune system’s fundamental cell types) and in the transition from monocyte to macrophage undergo an activation process that is regulated by the presence of specific proteins which then dictate its final form. Two major forms of mature macrophages have been identified:
- M1, known as “classically activated” macrophages; and
- M2, known as “alternatively activated” macrophages.
In most cases, the mature form of the macrophage plays an important role in promoting the health and well-being of the body. However, research into these two phenotypes has shown that the M2 sub-type can also be associated with increased tumor burden in some forms of cancer. These macrophages, called tumor-associated macrophages (TAMs), have been implicated in the development of multiple forms of cancer and mesothelioma, including pleural mesothelioma and peritoneal mesothelioma. Not only have they been shown to have an overall immunosuppressive effect, which allows the growth of tumor tissue to proceed without restraint, they have also been implicated in angiogenesis (the process by which new blood vessels are formed and tumors are supplied with the blood necessary for their growth) and growth-factor overexpression that some feel is responsible for “cell survival, invasion and metastasis.”
In light of these previous findings, the authors of this study were interested in learning what, if any, effect a reduction in the density of TAMs would have on tumor growth and progression. To investigate this, they studied a mouse population with malignant peritoneal mesothelioma and used intraperitoneal injections of liopsome-encapsulated clodronate (CLIP) to trigger apoptosis in the macrophages. Their injections were targeted at just the macrophages and not the actual mesothelioma cells and their testing confirmed this targeting was successful. Their results showed a clear benefit to macrophage depletion.
In nearly all cases of mice treated with CLIP versus the control therapies utilized, CLIP-treated mice showed significant reductions in tumor burden, tumor growth and tumor progression. Whether the test was looking at the future development of tumor tissue after having been exposed to the mesothelioma cell lines or in those mice who exhibited mesothelioma tumor tissue when the testing began, the depletion of TAMs showed a positive effect in the treated mice. The authors report that mice injected with CLIP showed a 4-fold reduction in the number of tumors and a 17-fold reduction in overall tumor burden. They also showed that the metastatic potential for mice treated with CLIP was significantly lowered than in mice for the control groups. For those mice who received CLIP after having already developed mesothelioma tumors, they too showed a marked reduction in tumor size and burden, although they did not show a reduction in metastatic potential as compared to the control groups.
The authors clearly state that their mouse studies show that TAMs are an important factor in the growth of mesothelioma. These macrophages seem to have important effects on growth factor expression, angiogenesis and tumor immunity and their reduction, using intraperitoneal CLIP injections, has been shown to have positive effects on reducing tumor burden and progression. In light of these findings, the authors call for the beginnings of human trials in patients who are unable to tolerate multimodal treatments.