The fibrotic and immune microenvironments as targetable drivers of metastasis

Abstract

Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced metastatic disease are still few and far between. Cancer cells do not exist in isolation: rather, they exist within a complex microenvironment composed of stromal cells and extracellular matrix. Within this tumour microenvironment exists an interplay between the two main stromal cell subtypes, cancer-associated fibroblasts (CAFs) and immune cells, that are important in controlling metastasis. A complex network of paracrine signalling pathways between CAFs, immune cells and tumour cells are involved at multiple stages of the metastatic process, from invasion and intravasation at the primary tumour site to extravasation and colonisation in the metastatic site. Heterogeneity and plasticity within stromal cell populations also contribute to the complexity. Although many of these processes are likely to be common to a number of metastatic sites, we will describe in detail the interplay within the liver, a preferred site of metastasis for many tumours. A greater understanding of these networks provides opportunities for the design of new therapeutic approaches for targeting the metastatic disease.

TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

“…Fibrotic TME actively contributes to the pro-tumoral activities for promoting angiogenesis, ECM remodelling, immunosuppression, inflammation, and tumor growth [ 13 , 75 ]. CAFs are highly present in TME of most cancers associated with worse prognosis [ 76 , 77 , 78 , 79 ].…”

“…Fibrotic TME is important in the development of primary and secondary drug resistance via various mechanisms [ 13 , 75 ], but the underlying mechanism is still largely unclear. TGF-β1 contributes to oxaliplatin resistance in human colorectal cancer via EMT [ 128 ].…”

“…Indeed, sole activation of TGF-β signaling is sufficient to cause fibrosis, e.g., forced overexpression of a constitutively active TGF-β receptor type I in murine skin is capable of inducing fibrosis [ 12 ]. Importantly, contribution of fibrotic signaling in the TME has recently been recognized and is suggested to be a new therapeutic target for blocking cancer progression [ 13 ]. This review summarized the pathogenic roles and underlying mechanisms of TGF-β signaling in cancer, particularly the fibrotic TME.…”

Tumor‐Associated Protrusion Fluctuations as a Signature of Cancer Invasiveness

“…In contrast, the complex native TME comprises host tumor and a diverse repertoire of stromal cells, including immune system cells, mesenchymal stem cells, adipocytes, endothelial cells, or fibroblasts, which synergistically interact with the primary tumor. [36,37] A single cell type was chosen because we aimed to provide a simplistic framework to quantitatively/qualitatively obtain evidences on how protrusion fluctuations regulate tumor invasiveness. The influence of other cell types in the modulation of such fluctuations may need to be assessed; this will help mimicking the physiological scenario in a more realistic manner.…”

Immune Responses against Disseminated Tumor Cells

“…Cancer cells and stroma can also secret chemokine ligand 2 (CCL-2) to recruit C-C chemokine receptor type 2 (CCR2 + ) monocytes in metastatic lesion, facilitating tumor seeding [ 67 ]. Furthermore, TAMs can foster a fibrotic microenvironment with increased endothelial permeability, thus nurturing colony development of disseminated cancer cells [ 68 ]. In a genetically engineered breast cancer mouse model, Prune-1 expression augmented the M2 polarization of TAMs through TGF-β enhancement and IL-17F secretion, thus facilitating lung metastasis [ 69 ].…”