Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma
Daniela PaňkováYulong ChenMasahiko TerajimaMark J. SchliekelmanBrandi N. BairdMonica FahrenholtzLi SunBartley J. GillTegy J. VadakkanMin P. KimYoung‐Ho AhnJonathon D. RoybalXin LiuEdwin R. ParraJaime Rodriguez‐CanalesIgnacio I. WistubaChad J. CreightonDon L. GibbonsJohn M. HicksMary E. DickinsonJennifer L. WestK. Jane Grande‐AllenSamir HanashMitsuo YamauchiJonathan M. Kurie
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Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCC) and lower lysine-aldehyde-derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration.CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.Keywords:
Cancer-Associated Fibroblasts
Lysyl Oxidase
Type I collagen
Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States.Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells.Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs.However, other important components of the PC stroma are inflammatory cells and endothelial cells.The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma.Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells.However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers.Hence, the precise role of the tumour stroma in PC remains to be elucidated.However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
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Abstract Lysyl oxidase (LOX) and LOX-like (LOXL) enzymes are key players in extracellular matrix deposition and maturation. LOX promote tumour progression and metastasis, but it may also have tumour-inhibitory effects. Here we show that orthotopic implantation of rat prostate AT-1 tumour cells increased LOX and LOXLs mRNA expressions in the tumour and in the surrounding non-malignant prostate tissue. Inhibition of LOX enzymes, using Beta-aminopropionitrile (BAPN), initiated before implantation of AT-1 cells, reduced tumour growth. Conversely, treatment that was started after the tumours were established resulted in unaffected or increased tumour growth. Moreover, treatment with BAPN did not suppress the formation of spontaneous lymph node metastases, or lung tumour burden, when tumour cells were injected intravenously. A temporal decrease in collagen fibre content, which is a target for LOX, was observed in tumours and in the tumour-adjacent prostate tissue. This may explain why early BAPN treatment is more effective in inhibiting tumour growth compared to treatment initiated later. Our data suggest that the enzymatic function of the LOX family is context-dependent, with both tumour-suppressing and tumour-promoting properties in prostate cancer. Further investigations are needed to understand the circumstances under which LOX inhibition may be used as a therapeutic target for cancer patients.
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Lysyl Oxidase
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Background and Objective Mechanical stretching modulates extracellular matrix ( ECM ) protein synthesis by periodontal ligament ( PDL ) cells. However, the mechanoregulation of lysyl oxidase ( LOX ), a key enzyme for collagen cross‐linking, is not fully understood. In the present study, we hypothesized that low‐level and high‐level mechanical stretching differentially regulates collagen deposition and the expression of LOX and the enzymes responsible for ECM degradation, such as MMP ‐2 in PDL cells. Material and Methods Human PDL cells were cultured on flexible‐bottom culture plates and subjected to cyclic mechanical stretching (3% and 10% elongation at 0.1 Hz) for 24 and 48 h in a Flexercell FX‐4000 strain unit. The levels of expression of type I collagen alpha 1 ( COL1A1 ), type III collagen alpha 1 ( COL3A1 ), lysyl oxidase ( LOX) , MMP2 and TIMP2 mRNAs were analyzed using an RT‐PCR technique. The cell layer and the culture medium were separately collected and processed for detection of the following ECM‐related molecules: (i) total collagen content using a Sircol dye‐binding method; (ii) LOX protein expression by western blotting; (iii) LOX activity using a fluorometric assay; and (iv) MMP‐2 enzyme activity by gelatin zymography. Results Low‐level (3%) mechanical stretching of PDL cells upregulated the expression of COL1A1 , COL3A1 and LOX mRNA s, enhanced the production of collagen and increased the LOX activity but did not change the level of expression of MMP2 or TIMP2 mRNA . The collagen content and LOX activity showed obvious elevation in the medium, but not in the cell layer. High‐level (10%) mechanical stretching downregulated COL1A1 mRNA but upregulated COL3A1 mRNA ; however, the effect on COL3A1 was smaller, and occurred earlier, compared with the effect on the COL1A1 gene. High‐level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNA s but did not change collagen production or LOX activity. Moreover, high‐level mechanical stretching increased the level of pro‐MMP‐2, especially in the cell layer. Conclusions This study substantiates the mechanoregulation of the expression of ECM‐related molecules in PDL cells. High‐level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNA s, but did not affect collagen production or LOX activity. In addition to increasing the transcription of COL1A1 , COL3A1 and LOX genes, low‐level mechanical stretching enhanced total collagen production and LOX activity, which should favor ECM stabilization. As an effective regulator of ECM remodeling, mechanical stretching can be exploited in periodontal regeneration and ligament tissue engineering via application of appropriate mechanical stimulation.
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Tumours are highly complex tissues composed of carcinoma cells and surrounding stroma, which is constructed by various different types of mesenchymal cells and an extracellular matrix (ECM). Carcinoma-associated fibroblasts (CAFs), which consist of both fibroblasts and myofibroblasts, are frequently observed in the stroma of human carcinomas, and their presence in large numbers is often associated with the development of high-grade malignancies and poor prognoses. Moreover, in human tumour xenograft models, CAFs extracted from the tumour are more capable of promoting tumour growth through their interactions with carcinoma cells when compared to those isolated from non-cancerous stroma. Taken together, these observations strongly suggest that CAFs actively contribute to tumour progression. In this review we highlight the emerging roles of these cells in promoting tumourigenesis, and we discuss the molecular mechanisms underlying their tumour-promoting capabilities and their cellular origin.
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Pancreatic cancer (PC) has an extremely high mortality with a five-year survival of only 5%. The cancer cells are accompanied by the desmoplastic stroma produced by cancer-associated fibroblasts (CAFs). Pancreatic stellate cells are the most important source of CAFs. Several studies indicate that the desmoplastic stroma reduces the effect of radio- and chemotherapy, but experimental reduction of desmoplasia and CAFs leads to more aggressive cancers. Hence, the exact role of desmoplasia in PC remains to be elucidated, and future studies should also include human pancreatic tissue.
Desmoplasia
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Stromal fibroblasts from 230 cancerous tumors of different localization were studied. Fibroblasts were located in the stroma of cancerous tumors relatively uniformly - on average 2430.9 133.7 per 1 mm2 stroma, but since the stroma occupied only a part of tumors, the number of fibroblasts per 1 mm2 histological preparation of neoplasm was somewhat lower and varied from 58.1 to 2772.0 (on average 1114.4 107.8), and in some cases fibroblasts were the prevailing cell type. The axial orientation of these stromal cells, especially in the areas of mature stroma, mostly coincided with the direction of collagen fiber bundles, and in the areas of edematous and disorganized connective tissue was often chaotic.
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