Abstract
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.
Highlights
Identification of a general and suitable target that is unambiguously oncogenic or tumor suppressive is a foundation on which cancer therapeutic strategies could be designed and developed.Fibronectin (FN) (Figure 1A) has long been proposed to play an important role in the pathobiology of cancer
The fast growing tumor cells in the primary tissues can secrete chemokines and exosomes to drive bone marrow-derived cells (BMDCs) that are recruited in the distant organs to establish premetastatic niche (PMN) where macrophages and CAFs are mainly responsible for the FN deposition in the extracellular matrices (ECMs) of PMN to prepare a suitable tumor microenvironments (TMEs) for the future extravasated metastatic disseminated tumor cells (DTCs). diFN: dimeric form of FN; EpiFN: FN expression in normal epithelial cells; SeFN: FN expression and surface assembly in the stimuli-induced senescence cells; ECMFN: FN deposition in ECM
circulating tumor cells (CTCs) clusters, that are often formed together with platelets, M2 macrophages, or neutrophils, can adhere to endothelia via binding to dipeptidyl peptidase IV (DPP IV) by pericellular FN matrix assembly (periFN) assembled on FNhigh CTCs, followed by extravasation and migration to either non-PMN locations or PMN which has early been established by the outgrowing tumor cells in the primary tumor cells
Summary
Identification of a general and suitable target that is unambiguously oncogenic or tumor suppressive is a foundation on which cancer therapeutic strategies could be designed and developed. When deposited into extracellular matrices (ECMs) in the immunosuppressive tumor microenvironments (TMEs) in which tumor cells are often the driving force to induce inflammatory responses, FN promotes early tumor progression [10,11,12,13,14,15] but is paradoxically correlated with a better prognosis [7,16,17,18,19] (Figure 1B,C) Before resolving such obviously paradoxical roles of FN in cancer development, it is of high risk to target FN for controlling cancer. The role ofpapers stromal intopromoting early tumor progression notgreen late boxes), metastasis Among 46 publications after 2000, 7 (15.2%) papers are related14to the role of (30.4%) papers are related to the role of stromal FN in promoting early tumor progression but not late cancerous FN in tumor suppression (in light green boxes), 25 (54.4%) papers are related to the role metastasis (in dark green boxes).
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