Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.

Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.