The tumor microenvironment plays an active role in cancer initiation, progression and dissemination. This complex microenvironment consists of cells, such as neoplastic, stromal and infiltrating immune cells. This cellular eco-system is supported by a-cellular components such as the extracellular matrix (ECM), which is a collection of proteins, glycoproteins and proteoglycans. Accumulated evidences show that abnormal ECM may influence cellular behavior such as differentiation, proliferation and migration and is a hallmark of many cancers.
Tumor associated macrophages (TAMs) constitute up to 50% of the tumor mass and are considered pivotal players in suppressing the immune response and mounting pro-tumoral functions. Among others, TAMs secrete enzymes capable of shaping the ECM tumoral landscape including serine proteases, cathepsins and matrix-metalloproteases. Yet, their effect on tumor development and invasion through ECM remodeling remain largely unknown.
We hypothesize that TAMs shape the tumor ECM during cancer progression and hence indirectly impact pathophysiological cell processes. Here, we utilized a novel murine model of colorectal cancer (CRC) based on the direct orthotopic implantation of MC38 CRC cells into the colonic lamina propria of either C57BL/6 WT mice, or Ccr2-/- mice lacking TAMs due to deficiency in monocyte recruitment. Scanning electron microscopy analysis of cell-free ECM scaffolds revealed that the ECM of WT tumors differ significantly from these of the Ccr2-/- mice, e.g. in the level of linearized collagen fibers detected. Moreover, mass spectrometry analysis revealed differences in ECM protein composition, namely in the ratio between collagen types composing this microenvironment. Importantly, using Affymetrix microarray and complementary RT-PCR approaches we defined the specific panel of ECM effector molecules expressed by sorted CRC-TAM subsets in comparison with their counterparts from steady state and inflamed colons. Overall, our integrated biophysical-immunologic analysis hold the promise to reveal key molecular mechanisms associated with the role of TAMs derived ECM remodeling in CRC.
