Matrix In Breast Cancer Research Articles

Eosinophilic Dermatoses: Cause of Non-Infectious Erythema after Volume Replacement with Diced Acellular Dermal Matrix in Breast Cancer?

Non-infectious erythema, or Red Breast Syndrome (RBS), has been observed on the skin where acellular dermal matrix was implanted, although the exact cause is yet to be determined. A total of 214 female patients underwent breast-conserving surgery (BCS) and volume replacement using diced acellular dermal matrix (dADM) for breast cancer between December 2017 and December 2018. After collecting and evaluating relevant clinical data, inflammation markers, along with NK cell status presented by IFN-γ secretion assay, were measured using ELISA. Nineteen patients (8.88%) presented with RBS after BCS and dADM use. A significant increase of platelet-to-lymphocyte ratio was noted in the non-RBS group (p = 0.02). Compared to the RBS group (p = 0.042), the WBC level of the non-RBS group showed significant decrease over time. Eosinophil counts increased significantly at follow-up but went up higher in the RBS group. Multivariate analysis showed preoperative chemotherapy significantly increased the hazard of RBS (OR 3.274, p = 0.047 and OR 17.098, p < 0.001, respectively). Though no causal relationship between RBS and immune status was proven, the results suggest an association between preoperative chemotherapy and RBS in addition to the possible role of eosinophilia in leading to eosinophilic dermatoses, which warrants further exploration and elucidation.

Investigating the contribution of hyaluronan to the breast tumour microenvironment using multiparametric MRI and MR elastography.

Hyaluronan (HA) is a key component of the dense extracellular matrix in breast cancer, and its accumulation is associated with poor prognosis and metastasis. Pegvorhyaluronidase alfa (PEGPH20) enzymatically degrades HA and can enhance drug delivery and treatment response in preclinical tumour models. Clinical development of stromal-targeted therapies would be accelerated by imaging biomarkers that inform on therapeutic efficacy in vivo. Here, PEGPH20 response was assessed by multiparametric magnetic resonance imaging (MRI) in three orthotopic breast tumour models. Treatment of 4T1/HAS3 tumours, the model with the highest HA accumulation, reduced T1 and T2 relaxation times and the apparent diffusion coefficient (ADC), and increased the magnetisation transfer ratio, consistent with lower tissue water content and collapse of the extracellular space. The transverse relaxation rate R2 * increased, consistent with greater erythrocyte accessibility following vascular decompression. Treatment of MDA-MB-231 LM2-4 tumours reduced ADC and dramatically increased tumour viscoelasticity measured by MR elastography. Correlation matrix analyses of data from all models identified ADC as having the strongest correlation with HA accumulation, suggesting that ADC is the most sensitive imaging biomarker of tumour response to PEGPH20.

Macrophages and Extracellular Matrix in Breast Cancer: Partners in Crime or Protective Allies?

Solid cancers such as breast tumors comprise a collection of tumor, stromal and immune cells, embedded within a network of tumor-specific extracellular matrix. This matrix is associated with tumor aggression, treatment failure, chemo- and radio-resistance, poor survival and metastasis. Recent data report an immunomodulatory role for the matrix in cancer, via the creation of niches that control the migration, localization, phenotype and function of tumor-infiltrating immune cells, ultimately contributing to escape of immune surveillance. Macrophages are crucial components of the immune infiltrate in tumors; they are associated with a poor prognosis in breast cancer and contribute to shaping the anti-tumor immune response. We and others have described how matrix molecules commonly upregulated within the tumor stroma, such as tenascin-C, fibronectin and collagen, exert a complex influence over macrophage behavior, for example restricting or enhancing their infiltration into the tumor, and driving their polarization towards or away from a pro-tumoral phenotype, and how in turn macrophages can modify matrix production in the tumor to favor tumor growth and metastasis. Targeting specific domains of matrix molecules to reinstate an efficient anti-tumor immune response, and effectively control tumor growth and spread, is emerging as a promising field offering a new angle for cancer therapy. Here, we review current knowledge on the interactions between tumor-associated macrophages and matrix molecules that occur within the tumor microenvironment of breast cancer, and discuss how these pathways can be targeted for new immunotherapies for hard to treat, desmoplastic tumors.

Cancer-associated fibroblasts support bone tropic metastasis by acting as coordinators between the tumor microenvironment and bone matrix in breast cancer.

Bone is a common site of metastasis for various types of cancer cells, including breast cancer, and the consequent skeleton-related events observed in patients are severe and often fatal. Currently, it is widely accepted that cancer-associated fibroblasts (CAFs) confer a metastasis-promoting property to breast cancer cells. Furthermore, clinical observations suggest that CAFs mediate the bone tropism of metastatic breast cancer cells. Therefore, a deeper understanding of the mechanism by which CAFs are involved in the bone-tropic metastasis of breast cancer can facilitate the study of the novel and effective therapeutic drugs for the corresponding targets. In this review, we focused on the coordinator role of CAFs in remolding breast cancer cells and remodeling the bone marrow during metastasis. We discussed the potential roles of the CXCL12/CXCR4 axis, the CAFs-CSCs reinforcing loop, and exosomes in this malignant process. In summary, in agreement with Paget's theory, CAFs play a pivotal role in bone colonization by breast cancer cells by providing a "fertile soil" for the "selected seeds" by influencing tumor-intrinsic characteristics and microenvironment (ME).

Abstract 1908: Using hierarchical clustering of differential gene expression patterns to study the contribution of the extracellular matrix in breast cancer

Abstract Breast cancer is the most frequently invasive cancer type among women worldwide, accounting for over 2 million new cases annually and 25% of all cancers diagnosed in women. Considering significant advances in the diagnostics and treatment of breast cancer it remains a leading cause of cancer mortality worldwide. The extracellular matrix (ECM) is a meshwork of fibrous proteins and proteoglycans that is essential for providing a physical framework and facilitating biochemical cues to maintain tissue homeostasis. However, the ECM also has a well-established role in tumour development and progression. Increasing evidence suggests that the ECM may impede targeted therapies and novel approaches that target the composition of the ECM may improve drug delivery and efficacy. Using the xCELLigence real time analysis platform, we monitored the growth of several breast cancer cell lines on the major fibrous proteins of the ECM to elucidate the contribution of individual ECM components on cell behaviour. Coupling this with endpoint assays, we have identified diverse adhesion, proliferation and migration profiles for each cell line on each substrate. RNA was extracted from cells in 2-Dimensional culture on 1) collagen, 2) fibronectin, 3) laminin and 4) stimulated by various growth factors and from cells in 3-Dimensional culture. Using qRT-PCR, we examined the expression of 40 genes that code for proteins known to directly or indirectly regulate the composition of the ECM. We determined that there is significant differential gene expression amongst each cell line in response to individual ECM components. Using a hierarchical clustering analysis of our gene panel, we have identified a strong relationship amongst cell lines maintained on collagen and fibronectin. We used STRING[1] analysis to help us refine a gene signature and are currently examining our gene set in patient tissue samples. Our hypothesis is that the composition of the ECM regulates gene expression and this correlates with advanced cancer stage. This work has the potential to create a clinically relevant gene signature to be used in the prediction of invasive cancers. Understanding how the ECM influences these proteins may provide information on the design of novel ECM targeted therapies in breast cancer. 1. Szklarczyk, D., et al., The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic acids research, 2017. 45(D1):p. D362-D368. Citation Format: Joanne Nolan, Amira F. Mahdi, Aoife J. Lowery, Colum P. Dunne, Patrick A. Kiely. Using hierarchical clustering of differential gene expression patterns to study the contribution of the extracellular matrix in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1908.

From transformation to metastasis: deconstructing the extracellular matrix in breast cancer.

The extracellular matrix (ECM) is a guiding force that regulates various developmental stages of the breast. In addition to providing structural support for the cells, it mediates epithelial-stromal communication and provides cues for cell survival, proliferation, and differentiation. Perturbations in ECM architecture profoundly influence breast tumor progression and metastasis. Understanding how a dysregulated ECM can facilitate malignant transformation is crucial to designing treatments to effectively target the tumor microenvironment. Here, we address the contribution of ECM mechanics to breast cancer progression, metastasis, and treatment resistance and discuss potential therapeutic strategies targeting the ECM.

Abstract 3215: Microenvironmental impact on breast cancer cell dormancy and drug sensitivity in a 3D model

Abstract Solid tumor contains heterogeneous and complex extracellular matrix environment. Tumor phenotypes are highly dependent on complex interactions with the surrounding cells and the ECM. Tumor dormancy is commonly observed clinically, however, the sources of dormant cells are unknown and their biological properties unclear. Recent evidence suggests that tumor residues are always ECM associated. Ioundt is important to replicate in vivo tumor environment with defined extracellular matrix in 3D environment to study tumor cell distinctive states. In this study, we engineered a construct by using transglutaminase crosslinked gelatin to recapitulate the in vivo breast cancer milieu and mimicking distinctive density of breast cancer matrix. First, we found that 3D matrix restriction had significant impacts on proliferation rate, cell morphology, tumoroid size and protein expressions of breast cancer cell MDA-MB-23 when growing in 3D matrices with different stiffness. Besides MDA-MB-231, ten different other tumor cell types were placed in a spectrum of gel conditions and their proliferation profiles have been established. We therefore could setup tumor culture models specifically for proliferative or dormant cells by changing gel concentration or crosslinking rates. Second, we used exogenous collagenase to mimic autocrine or paracrine proteases activity to mimic ECM degradation in dynamic tumor progression. We found that alteration of matrix mechanical restriction by enzyme degradation or ECM deposition could reversibly induce breast cancer cell from dormancy to proliferative or vise versa. Third, we tested the drug sensitivity at different matrix conditions. Both paclitaxel and gemcitabine displayed significant efficacy when cells in the highly proliferative state. However, paclitaxel had strong impact on breaking up tumor clusters but with little effect on inducing their apoptosis. Gemcitabine could diffuse into different size cell clusters to induce apoptosis. When cells were adopted dormant state, they showed less drug sensitivity for both drugs. We further demonstrate that there was no additive effect of paclitaxel and gemcitabine at all tested conditions. In conclusion, we setup a tailorable 3D model to study tumor cell proliferative and dormant states by taking into consideration of cell type preference on ECM conditions. There is an urgent need for tools to reliably and quickly predict responses of patients’ cancers to treatment regimens. With this in vitro drug screening model, it has potential to predict the drugs in single use or in combination effect. Note: This abstract was not presented at the meeting. Citation Format: Bo Han, Josephine Fang, Shih-Jye Tan, Yi-Chen Wu. Microenvironmental impact on breast cancer cell dormancy and drug sensitivity in a 3D model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3215. doi:10.1158/1538-7445.AM2015-3215

Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

The biology of breast cancer is closely releted to sex steroid hormones. Estrogen receptor beta is overexpressed in around 70% breast cancer cases, referrd to as "ER positive". Estrogens bind to estrogen receptor and stimulate the transcription of genes involved in control of cell proliferation. Moreover, estrogens may induce growth factors and components of extracellular matrix and interact with them in a complex manner. Extracellular matrix and integrins play an important role in cell functions and their aberrant expressions are implicated in breast cancer development, invasion and metastasis. ER beta is certainly associated with more differentiated tumors, while evidence of role of ER beta is controversial. The highly invasive breast cancer ER beta negative cell line MDA-MB 231 can be the model of exam the role of ER beta in breast cancer. The aim of this study was to examine the role of activation of ER beta on the metabolism of the extracellular matrix and the expression of beta-1 integrin in the breast cancer cell line MDA-MB 231. The cells were exposed on the estradiol, tamoxifen, raloxifen and genisteina in dose dependent concentrations. To determine the relative rate of collagen syntesis we measured the time-dependent reduction of collagen-bound radioactivity after pulse-chase labeling with [3 H] prolina by Peterkofsky methods. The expression of beta-1 integrin was determine by Western blot analysis. The activity of MMP2 and 9 were measured using gelatin zymography with an image analysis system. Our data suggest on the role of estrogen receptor beta on the metabolism of extracellular matrix in the breast cancer line MDA - MB 231. Estradiol and SERMs regulate the expression of ECM proteins: collagen, integrins and enhance activity of metaloproteinases 2 and 9.

Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis

Lumican is a member of a small leucine-rich proteoglycan family, and it is reportedly overexpressed in human breast cancer. The expression of lumican in the extracellular matrix in breast cancer is associated with a high tumor grade, low estrogen receptor levels and young age. Lumican expression has been previously reported in colorectal cancer, but the role of lumican in the tumor is not well understood. In this study, we examined the expression and role of lumican in advanced colorectal cancer. Immunohistochemical staining was performed on 158 patients who underwent curative surgery for advanced colorectal cancer with lymph node metastasis. In the normal colorectal tissues, lumican immunoreactivity was observed in the fibroblasts and neural cells, but not in the colorectal epithelial cells. Lumican was localized in the cytoplasm of the cancer cells and its overexpression was detected in 99 of the 158 (62.7%) colorectal cancer patients. Clinicopathologically, there was no association of lumican expression with age, sex, histological typing, or venous and lymphatic invasion. However, lumican expression tended to correlate with the spread of lymph node metastasis and the depth of tumor invasion (p=0.136 and 0.135, respectively). Furthermore, the survival rate was significantly lower in patients with a high lumican expression level than in those with a low lumican expression level (p=0.048). These results indicate that lumican expression is a potential prognostic factor in patients with advanced colorectal cancer with nodal metastasis.

Role of the nuclear matrix in breast cancer.

The mammalian nucleus contains approximately 2 cm of DNA packed into a nucleus that is 10 microns in diameter. The packaging of DNA into the nucleus is organized by the nuclear matrix, the RNA-protein skeleton of the matrix. The nuclear matrix is the scaffold that organizes DNA at a structural as well as a functional level [1]. By organizing DNA in both structural and functional manners, the nuclear matrix plays a critical role in normal cellular function. Several reports have now demonstrated that the nuclear matrix is altered in cancer cells and is intimately involved in the function of several oncogenes. Defining how the nuclear matrix is involved in the process of cell transformation has implications not only for understanding malignancy, but also for the development of new biomarkers for diagnosis and prognosis.KeywordsBreast Cancer TissueNormal Breast TissueNuclear MatrixMatrix Attachment RegionLaryngeal Squamous Cell CarcinomaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.