Monocyte-derived macrophage assisted breast cancer cell invasion as a personalized, predictive metric to score metastatic risk

Abstract

Patient-to-patient variability in breast cancer progression complicates clinical treatment decisions. Of women undergoing prophylactic mastectomies, many may not have progressed to indolent forms of disease and could have benefited from milder, localized therapy. Tumor associated macrophages contribute significantly to tumor invasion and metastasis, with cysteine cathepsin proteases as important contributors. Here, a method is demonstrated by which variability in macrophage expression of cysteine cathepsins, their inhibitor cystatin C, and kinase activation can be used to train a multivariate model and score patients for invasion risk. These enzymatic profiles were used to predict macrophage-assisted MCF-7 breast cancer cell invasion in the trained computational model. To test these predictions, a priori, signals from monocytes isolated from women undergoing mastectomies were input to score their cancer invasion potential in a patient-specific manner, and successfully predicted that patient monocytes with highest predicted invasion indices matched those with more invasive initial diagnoses of the nine patients tested. Together this establishes proof-of-principle that personalized information acquired from minimally invasive blood draws may provide useful information to inform oncologists and patients of invasive/metastatic risk, helping to make decisions regarding radical mastectomy or milder, conservative treatments to save patients from hardship and surgical recovery.

Ovarian Cancer Cells Direct Monocyte Differentiation Through a Non-canonical Pathway

“…One possible mechanism for this is tumor cell production of hyaluronic acid, which leads to increased cholesterol efflux in macrophages; the resulting alteration in macrophage lipid rafts led to increased gene expression in response to exogenous IL-4 and suppressed gene expression in response to IFN (63). A key difference between our work and these studies is that most prior studies of macrophage polarization use monocyte-derived macrophages produced by canonical differentiation with MCSF, rather than tumor cell-directed differentiation (64). In the paradigm of full differentiation and polarization by tumor cells alone, our results do not support a clear role for TGFα in polarization, as the primary effect of inhibiting TGFα is the loss of CD68+ macrophages rather than a shift in the percentage of CD163+ macrophages.…”

Applying nanomedicine in maladaptive inflammation and angiogenesis

“…However, once monocytes adhere, they infiltrate into the lesions and differentiate into macrophages, which possess an inflammatory phenotype and secrete large amounts of proteases, inflammatory cytokines, reactive radicals, and auto- and paracrine signaling molecules [227–229]. These “flaring” molecules drive lesion remodeling, invasiveness (and metastasis in the case of cancer), and can induce a phenotypical change in preexisting macrophages and other cells[230–232].…”

PACMANS: A bioinformatically informed algorithm to predict, design, and disrupt protease‐on‐protease hydrolysis

“…Of particular interest, cathepsins K, L, S, and V share 60% sequence homology and among them, include the most potent mammalian collagenase, cathepsin K, and most potent mammalian elastase, cathepsin V . These four cathepsins have been implicated in many tissue destructive pathologies such as cancer metastasis, osteoporosis, atherosclerosis, rheumatoid arthritis, endometriosis, and tendinopathy . Consequently, these proteases have redundancy in substrate cleavage preferences.…”