Density of tumor-associated macrophages (TAMs) and expression of their growth factor receptor MCSF-R and CD14 in canine mammary adenocarcinomas of various grade of malignancy and metastasis

Abstract

Several years ago, the presence of macrophages in the tumor microenvironment was thought to be an inflammatory response to kill the cancer cells. Now, this is clear that the inflammatory cells that exit blood vessels and migrate to the tumor tissue play an important role in cancer progression. Various cells present in the tumor microenvironment enhance cancer growth and invasiveness by secretion of tumor-enhancing products. That is why tumors should not be treated as only aggregates of cancer cells but as separate structures. Macrophages form a major component of the inflammatory infiltration in tumors, where they are termed tumor-associated macrophages (TAMs).To the best of our knowledge, up-to-date there were no studies on tumor associated macrophages and the role of the tumor microenvironment in tumor invasion/metastasis in dogs. This is the first study performed to asses if the number of TAMs and expression of MCSF-R (macrophages colony stimulating factor receptor) and CD14 (LPS co-receptor) are associated with the grade of tumor malignancy and its ability to metastasize. We have performed immunohistochemical analysis of 50 canine mammary adenocarcinomas of various grade of malignancy (1 st , 2 nd , 3 rd ) and tumors that gave local or distant metastases.The results indicate that in dogs, similarly to humans and mice, the number of tumor associated macrophages is related to the cancer ability to metastasize. Our results also indicate that the expression of MCSF-R and, what is particularly new finding, CD14 is associated with tumor malignancy and its ability to metastasize. Hence, these molecules play a role in tumor progression, metastasis and microenvironment interactions. These results show that in dogs we should treat the tumor as a whole organ rather than just try to eliminate the cancer cells.

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

“…Contrary to this study, another group showed that the relative percentage of CD4 + T-cells was higher in canine mammary tumors that metastasized, whereas CD8 + T-cells percentage was higher in tumors that did not metastasize [65, 66]. In terms of TAMs, their density was significantly higher in canine mammary adenocarcinomas that metastasized [64]. Furthermore, a microarray analysis to determine the global gene expression of a coculture of canine macrophages and canine mammary cancer cells showed an upregulation of genes involved in angiogenesis in TAMs and an increase in the migratory and invasive capabilities of cancer cells [95].…”

“…There are few studies in canine mammary cancer regarding the influence of immune cells in tumor invasion and metastasis [55, 64, 95]. The role of lymphocytes and macrophages in canine mammary tumor metastasis is not fully understood.…”

Global gene expression profiles of canine macrophages and canine mammary cancer cells grown as a co-culture in vitro

“…For example, co-expression of CSF-1 and its receptor can be found in 50% of late stage breast and 70% of endometrial cancers [50,51]. During the course of our previous studies we found the CSF-1R expression in canine mammary cancer cells (Figure 10), as well as in tumour-associated macrophages [52]. The results of the studies of Kirma et al [53] suggest that the CSFs might have an autocrine role through CSF1R in epithelial tumour cells promoting their invasiveness into the surrounding matrix [54,55].…”

Influence of lymphocytes T and myeloid-derived suppressor cells on inhibition of antitumor response

“…U myszy zahamowanie ufosforylowanej formy STAT3 (p-STAT3) zmniejszyło liczbę mieloidalnych komórek supresoworych w guzie. U psów z nowotworem gruczołu sutkowego została wykazana bezpośrednia zależność pomiędzy liczbą mieloidalnych komórek supresorowych, ekspresją p-STAT3 a predyspozycją komórek nowotworowych do przerzutowania (18,29). W przerzutujących guzach gruczołu sutkowego suk liczba mieloidalnych komórek supresorowych i ekspresja p-STAT3 istotnie ze sobą korelują.…”