Hypercoagulability, a major complication of metastatic cancers, has usually been treated with heparins from natural sources, or with their synthetic derivatives, which are under intense investigation in clinical oncology. However, the use of heparin has been challenging for patients with risk of severe bleeding. While the systemic administration of heparins, in preclinical models, has shown primarily attenuating effects on metastasis, their direct effect on established solid tumors has generated contradictory outcomes. We investigated the direct antitumoral properties of two sulfated fucans isolated from marine echinoderms, FucSulf1 and FucSulf2, which exhibit anticoagulant activity with mild hemorrhagic potential. Unlike heparin, sulfated fucans significantly inhibited tumor cell proliferation (by ~30–50%), and inhibited tumor migration and invasion in vitro. We found that FucSulf1 and FucSulf2 interacted with fibronectin as efficiently as heparin, leading to loss of prostate cancer and melanoma cell spreading. The sulfated fucans increased the endocytosis of β1 integrin and neuropilin-1 chains, two cell receptors implicated in fibronectin-dependent adhesion. The treatment of cancer cells with both sulfated fucans, but not with heparin, also triggered intracellular focal adhesion kinase (FAK) degradation, with a consequent overall decrease in activated focal adhesion kinase levels. Finally, only sulfated fucans inhibited the growth of B16-F10 melanoma cells implanted in the dermis of syngeneic C57/BL6 mice. FucSulf1 and FucSulf2 arise from this study as candidates for the design of possible alternatives to long-term treatments of cancer patients with heparins, with the advantage of also controlling local growth and invasion of malignant cells.

Mammography is an essential breast cancer screening tool that uses low doses of ionizing radiation. Determining whether such exposures modulate cellular processes associated with epithelial plasticity remains important. This preliminary study investigated whether clinically relevant radiation doses (≈2.14 mGy per exposure) influence epithelial-mesenchymal transition (EMT)-associated markers and motility in breast cell lines. Human breast cell lines MCF-10A (non-tumorigenic), MCF-7 (luminal, ER⁺), and MDA-MB-231 (triple-negative) were exposed to single (2.14 mGy) or repeated (2.14 + 2.14 mGy) doses. Exposure was defined using a Monte Carlo-estimated glandular-equivalent dose derived from a breast-equivalent phantom under mammographic conditions. EMT-associated markers (E-cadherin, fibronectin, vimentin), collective migration, extracellular matrix invasion, MMP-2/9 activity, and transendothelial migration were assessed. Low-dose irradiation induced cell-specific modulation of EMT-associated markers and motility (p-values correspond to single and repeated exposures, respectively). In MCF-10A cells, E-cadherin expression decreased (p = 0.0025; p = 0.028). A fibronectin degradation pattern was observed under both regimens; however, total band quantification (220 kDa subunit plus smaller fragments) was unchanged. Collective migration increased modestly (p < 0.05), while invasion through a basement membrane matrix increased markedly (p < 0.0001), and MMP-9 activity decreased (p < 0.0001). In MCF-7 cells, irradiation increased fibronectin (p = 0.05, repeated doses), enhanced collective migration (p < 0.05; p < 0.001), abolished MMP-2 activity in controls (in both treatments), and reduced MMP-9 activity (p < 0.0001), without altering invasion. In MDA-MB-231 cells, vimentin expression was upregulated after repeated exposures (p = 0.0067), while fibronectin expression decreased (p = 0.035; p = 0.046). Matrix invasion increased after single and repeated exposures (p < 0.05; p < 0.0001), MMP-9 activity increased after single exposure (p < 0.0001), and transendothelial migration decreased after single and repeated exposures (p < 0.01; p < 0.0001), without changes in collective migration. MMP-2 activity was undetectable in MCF-10A and MDA-MB-231 cells. Mammography-equivalent radiation doses were associated with lineage-dependent modulation of EMT-associated markers and cellular motility in vitro, indicating context-dependent phenotypic effects of clinically relevant low-dose radiation.

Altered extracellular matrix (ECM), a hallmark of solid tumors, affects cellular survival, migration and differentiation. Typically viewed as tumor-suppressive, evidence suggests that apoptosis can also generate pro-tumoral signals. We previously showed that ECM from high-grade astrocytomas induces extensive endothelial anoikis, while a surviving subpopulation fails to form tubular structures (tubulogenesis-defective endothelial cells, or TDECs). We combined functional assays with whole-cell proteomics to investigate this response. Using real-time video microscopy, we found that apoptotic endothelial cells induced by tumor ECM attracted migrating endothelial cells and guided sprouting. Conditioned media from apoptotic endothelial cells contained a 2.8-fold increase in extracellular vesicles (EVs) relative to autologous ECM-primed endothelial cells. Although both EV populations improved TDEC tubulogenesis, only EVs produced upon tumor-ECM stimulation induced TDEC migration—a property lost when using EVs secreted by endothelial cells growing on TN-C-depleted matrices. Proteomic profiling revealed that TDECs shift from an adhesion-anchored to a microtubule-rich and glycolytically rewired phenotype, with upregulation of vesicle-trafficking regulators (ARF1/3/4, ANXA2/5), migration drivers (RAC1/3, RHOA/C, WDR1, FSCN1) and glycolytic enzymes (ENO1, ALDOA, PKM, LDHA), alongside the suppression of integrin- and cytoskeletal-anchoring proteins. Collectively, these findings indicate that tumor-ECM-driven endothelial apoptosis generates reversible reprogramming and an EV-mediated autocrine mechanism that may favor angiogenic balance.