Phagocyte—extracellular matrix crosstalk empowers tumor development and dissemination

Abstract

Phagocytes, such as tumor-associated macrophages (TAMs) and tumorassociated neutrophils (TANs), are abundant in the stroma of experimental and human tumors and are locally educated to mediate important biological functions that profoundly affect tumor initiation, growth, and dissemination. Of considerable importance is the noncellular component of the tumor microenvironment, namely-the extracellular matrix (ECM). This milieu is often overlooked due to its complexity and vast heterogeneity. Biophysical and biomechanical cues provided by the dynamically evolving tumorigenic ECM fundamentally modulate every behavioral facet of the cancer cells and of associated stromal cells. In this review, we discuss the intricate interplay between phagocytes and ECM that are lined up to support tumor progression. TAMs and TANs shape the tumorigenic ECM by providing key matrix-remodeling enzymes and structural proteins and in turn, the altered tumor ECM modulates their migration and function. A better mechanistic comprehension of this reciprocal dependence has exciting implications for the development of new therapeutic options for cancer.Abbreviations 3D, Three-dimensional; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

“…Another prominent feature of solid tumors is the remodeling in the extracellular matrix (ECM), through degradation or deposition of ECM constituents, that dictates the degree of tumor growth, neovascularization, intravasation of metastatic tumor cells, and metastatic niche establishment . Interestingly, both TAMs and TANs are critical in ECM remodeling …”

“…ECM degrading proteases, such as MMPs, ADAMs (A Disintegrin And Metalloproteinase), and related proteinases, are highly expressed in TAMs and TANs and known to regulate tumorigenesis, angiogenesis, and metastasis . MMP‐mediated cleavage of collagen generates proline‐glycine‐proline (PGP) tripeptides, which have been shown to increase the directionality of migrating neutrophils, suggesting a role for MMPs in regulating neutrophil accumulation in the TME.…”

“…The excessive growth of connective tissue, referred to as desmoplasia and a feature of many types of cancers, is known to be regulated by TAMs through the upregulation of matrix‐related glycoproteins such as osteopontin (OPN), osteoactivin, fibronectin, and SPARC . Interestingly, OPN has been reported to colocalize with TANs in human glioblastoma samples, suggesting TANs as a probable source of OPN .…”

“…Interestingly, TRMs, but not BMDMs, express profibrotic genes in PDAC models . Apart from directly producing collagen and related ECM proteins, TAMs also regulate CAFs to promote collagen production . Similarly, TANs have been reported to exhibit an indirect stimulatory effect on obesity‐associated desmoplasia in a murine model of PDAC where a cross‐talk between TANs, cancer associated adipocytes and pancreatic stellate cells (PSC), partly through soluble factors like IL‐1β, activates PSC and leads to pronounced collagen‐I deposition .…”

“…155 Apart from directly producing collagen and related ECM proteins, TAMs also regulate CAFs to promote collagen production. 142,154 Similarly, TANs have been reported to exhibit an indirect stimulatory effect on obesity-associated desmoplasia in a murine model of PDAC where a cross-talk between TANs, cancer associated adipocytes and pancreatic stellate cells (PSC), partly through soluble factors like IL-1 , activates PSC and leads to pronounced collagen-I deposition. 157 Although the ability of TAMs and TANs to detect and translate mechanical changes in the ECM into biochemical signals to regulate tumor growth has been proposed and investigated, more targeted studies are required to understand the specific contribution and the extent of physical modification of the TME by innate immune cells.…”