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Background Recently, a marker for predicting metastasis or recurrence precisely in solid cancers has been focused on instead of the identification of isolated tumor cells detected by epithelial genes in circulating system. We identified a candidate marker in gastric cancer by microarray and validated it through a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Methods To identify metastasis-related genes, we performed cDNA microarray analysis of total RNA from whole bone marrow blood from six cases with metastasis and three cases without metastasis. We determined clinical significance of the identified gene by microarray analysis with quantitative real-time RT-PCR in bone marrow and peripheral blood from 810 cases of gastric cancer. Results We focused on membrane type 1 matrix metalloproteinase ( MT1-MMP ) as a candidate marker to predict distant metastasis among identified genes. MT1-MMP -positive expression in peripheral blood was associated with incidence of peritoneal dissemination, lymphatic permeation, vascular permeation, and lymph node metastasis. MT1-MMP -positive expression in bone marrow was also significantly related to the incidence of distant metastasis and peritoneal dissemination. Conclusion The expression of MT1-MMP in peripheral blood from gastric cancer cases was a powerful indicator of distant metastasis especially for peritoneal dissemination. The presence of MT1-MMP -expressing cells in bone marrow indicated higher risk for distant metastasis in gastric cancer cases.

Background Expression of matrix metalloproteases 2, 9 and 14 (MMP-2, MMP-9, MMP-14), tissue inhibitors of metalloprotease 1 and 2 (TIMP-1, TIMP-2) and vascular endothelial growth factor A (VEGF-A) is involved in tumor invasion and metastasis via extracellular matrix degradation and angiogenesis. This study aimed to assess whether the expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 in tumors and in the adjacent stroma is associated with cervical cancer prognosis. Methods This study analyzed a retrospective cohort of 64 patients. Protein expression was previously obtained by immunohistochemistry from biopsies containing both tumor and stroma. The expression and percentage of stained cells were categorized as high or low according to the cutoff points by using ROC curves. The follow-up data was collected from diagnosis to the last clinical visit. Clinical status categorized as alive without disease, alive with disease, death due to other causes, and death from the disease. The relative risk of death from the disease was evaluated according to the proteins expression using a cause-specific Cox regression model with a 95% confidence interval (95%CI). For the significant associations ( p  < 0.05), survival curves of patients with low and high expression were plotted for the competing risk survival curve analyses. Results High expression levels of stromal MMP-2 (RR; 95%CI: 3.91; 1.17–13.02) and stromal TIMP-2 (RR, 95%CI: 8.67; 1.15–65.27) were associated with a greater relative risk of death from the disease and with lower survival ( p  = 0.03; p  = 0.04) than lower expression levels. Low expression levels of stromal MMP-9 (RR, 95%CI: 0.19; 0.05–0.65) and tumoral MMP-9 (HR, 95%CI: 0.19; 0.04–0.90) were protective factors against death from the disease and were associated with poorer survival. Conclusions High expression levels of MMP-2 and TIMP-2 in the stroma were significantly associated with poor survival in cervical cancer patients. High expression of MMP-9 was associated with a favorable cervical cancer prognosis.

Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade and replace the collagen-containing injured tissue. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion. We observe close interactions between protruding border-zone cardiomyocytes and macrophages, and show that macrophages are essential for extracellular matrix remodeling at the wound border zone and cardiomyocyte protrusion into the injured area. Single-cell RNA-sequencing reveals the expression of mmp14b , encoding a membrane-anchored matrix metalloproteinase, in several cell types at the border zone. Genetic mmp14b mutation leads to decreased macrophage recruitment, collagen degradation, and subsequent cardiomyocyte protrusion into injured tissue. Furthermore, cardiomyocyte-specific overexpression of mmp14b is sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data provide important insights into the mechanisms underlying cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. Adult zebrafish are capable of heart regeneration, but how the collagenous injury site is replaced remains unclear. Here they provide an in-depth analysis of cardiomyocyte protrusion during zebrafish cardiac regeneration and highlight the role of macrophages and Mmp14b in ECM remodeling to support replacement of injured tissue with new cardiomyocytes.

The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.

Skin cutaneous melanoma (SKCM) and squamous cell carcinoma (SCC) are two prevalent forms of skin cancer, both characterized by extensive remodeling of the extracellular matrix (ECM), which facilitates tumor progression and metastasis. To investigate ECM-related gene expression alterations in SCC and assess their diagnostic and prognostic relevance in SKCM by integrating transcriptomic data with clinical outcomes. RNA-sequencing data from NCBI Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes in SCC. Key findings were validated in The Cancer Genome Atlas (TCGA) SKCM dataset. Functional enrichment and protein–protein interaction (PPI) analyses were conducted to identify ECM-related pathways and hub genes. Matrix metalloproteinases MMP7, MMP11, and MMP14 were significantly upregulated in SCC and showed elevated expression in primary SKCM tumors, confirmed by RT-qPCR analysis. Functional enrichment revealed dysregulation of ECM–receptor interaction and IL-17 signaling pathways. PPI analysis identified MMP14 as central hub interacting with TIMPs, CD44, and FURIN. Kaplan–Meier survival analysis showed that elevated MMP11 and MMP14 expression correlated with worse overall survival. ROC curve analysis confirmed their strong diagnostic value, with MMP14 achieving an AUC of 0.955. MMP7, MMP11, and MMP14 play key roles in skin cancer progression. They show strong potential as diagnostic and prognostic biomarkers and may serve as therapeutic targets in SCC and SKCM.

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.

Ovarian carcinoma is one of the fatal gynecological cancers due to the lack of clinical symptoms at earlier stages of disease leading to metastasis and lower survival rates. Hence, an in-depth exploration of the mechanisms of metastasis facilitates the development of novel-targeted therapeutic strategies to treat the disease. Research studies have reported that three predominant Matrix metalloproteinases (MMPs), namely, MMP14, MMP2 and MMP9 can induce the migration of ovarian cancer cells, Epithelial-Mesenchymal transition, breakdown of extracellular matrix, upregulation of expression of transcription factors etc. in the microenvironment of ovarian tumors. In our current research, these predominant MMPs were used as target proteins and docked with potential anti-cancerous phyto-nutraceuticals present in Allium ascalonicum species. Allium ascalonicum , commonly referred to as Shallots is being used in various cuisines worldwide and is still largely unexploited for its anti-cancer properties. Docking results, revealed three potential phyto-nutraceuticals, of which, 1-[[3,5-bis(phenylmethoxy)phenyl]methyl]-6-methoxy-2-methyl-3,4-dihydro-1 H -isoquinoline, an isoquinoline alkaloid was considered the best, since it exhibits significant binding affinity when compared to that of the standard drug, Melphalan. Molecular dynamic simulation studies exhibited that MMP2 is highly flexible and can form more stable interactions. Furthermore, simulation studies of finest interaction pose of the target MMPs with the best phyto-nutraceutical, revealed stable interactions and occurrence of conformational changes. The results, also suggested that, the best phyto-nutraceutical of Allium ascalonicum is a novel isoquinoline alkaloid, with favorable bioavailability scores that interact with target MMPs to control the progression and metastasis of ovarian cancer, proposing the prospect of formulating it into sustainable medications for treating metastasized Ovarian Cancer.

Overexpression of the transmembrane matrix metalloproteinase MT1-MMP/MMP14 promotes cancer cell invasion. Here we show that MT1-MMP-positive cancer cells turn MT1-MMP-negative cells invasive by transferring a soluble catalytic ectodomain of MT1-MMP. Surprisingly, this effect depends on the presence of TKS4 and TKS5 in the donor cell, adaptor proteins previously implicated in invadopodia formation. In endosomes of the donor cell, TKS4/5 promote ADAM-mediated cleavage of MT1-MMP by bridging the two proteases, and cleavage is stimulated by the low intraluminal pH of endosomes. The bridging depends on the PX domains of TKS4/5, which coincidently interact with the cytosolic tail of MT1-MMP and endosomal phosphatidylinositol 3-phosphate. MT1-MMP recruits TKS4/5 into multivesicular endosomes for their subsequent co-secretion in extracellular vesicles, together with the enzymatically active ectodomain. The shed ectodomain converts non-invasive recipient cells into an invasive phenotype. Thus, TKS4/5 promote intercellular transfer of cancer cell invasiveness by facilitating ADAM-mediated shedding of MT1-MMP in acidic endosomes. The matrix metalloprotease MT1-MMP drives cancer metastasis. Here, the authors demonstrate how invasive cancer cells instigate non-invasive neighbouring cells to become degradative and invasive by transferring catalytically active MT1-MMP fragments.

Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown. This study demonstrates the functional role of extracellular and intracellular collagen degradative pathways in two different settings of cervical remodeling: physiological term remodeling and inflammation-mediated premature remodeling. Extracellular collagen degradation is achieved by the activity of fibroblast-derived matrix metalloproteases MMP14, MMP2, and fibroblast activation protein (FAP). In parallel, we demonstrate the function of an intracellular collagen degradative pathway in fibroblast cells mediated by the collagen endocytic mannose receptor type-2 (MRC2). These pathways appear to be functionally redundant as loss of MRC2 does not obstruct collagen turnover or cervical function in pregnancy. While both extracellular and intracellular pathways are also utilized in inflammation-mediated premature cervical remodeling, the extracellular collagen degradation pathway uniquely employs fibroblast and immune-cell-derived proteases. In sum, these findings identify the dual utilization of two distinct degradative pathways as a failsafe mechanism to achieve continuous collagen turnover in the cervix, thereby allowing dynamic shifts in cervical tissue mechanics and function.

Geleophysic dysplasia (GD) is characterized by short stature, brachydactyly, joint limitations, a distinctive facial appearance, as well as cardiac and respiratory dysfunction that can be life-threatening. GD is caused by pathogenic variants in the ADAMTSL2 , FBN1 , or LTBP3 genes. While dermal fibroblasts derived from affected individuals have shown poor organization of the extracellular matrix (ECM), it remains elusive how the disorganized ECM contributes to GD pathogenesis. To understand the molecular mechanisms in GD, we isolated and characterized primary human dermal fibroblasts from affected individuals with ADAMTSL2 and FBN1 variants. We found that the secretion of ECM proteins including ADAMTSL2, FBN1, and Fibronectin were impaired in GD fibroblasts. Increased cell migration was observed in GD fibroblasts carrying ADAMTSL2 or FBN1 variants, which was associated with up-regulation of MMP-1 and MMP-14, two proteases related to cell mobility. The enhanced cell migration and up-regulation of MMP-1 and MMP-14 were corroborated in mouse primary dermal fibroblasts carrying pathogenic variants in Adamtsl2 and in lung and heart tissues from Adamtsl2 - knockout mice. A pan MMP inhibitor, GM6001, inhibited the migration of GD fibroblasts. Overall, our results suggest that MMP-1/-14 up-regulation play a role in the development of GD and may be utilized as a treatment target.