Tumor-Stroma Interaction of Human Pancreatic Cancer: Acquired Resistance to Anticancer Drugs and Proliferation Regulation Is Dependent on Extracellular Matrix Proteins

Miyamoto, Hidenori; Murakami, Tatsuya; Tsuchida, Kunihiro; Sugino, Hiromu; Miyake, Hidenori; Tashiro, Seiki

doi:10.1097/00006676-200401000-00006

Cited by 211 publications

(169 citation statements)

References 23 publications

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“…In agreement with previous studies, our results also indicate that MiaPaCa-2 cells do not attach to types I or IV collagen, and they do not express the a 2 integrin subunit (Sawai et al, 2001;Miyamoto et al, 2004). In fact, it has been recently shown that attempts to grow MiaPaCa-2 cells on type I collagen substrates resulted in apoptosis (Vaquero et al, 2003).…”

Section: Discussionsupporting

confidence: 93%

“…While expression of the a 2 integrin subunit has been demonstrated previously for most of these cell lines (Lohr et al, 1996;Sawai et al, 2001;Miyamoto et al, 2004), to our knowledge, this is the first demonstration that the CFPAC cell line is also a 2 integrin subunit positive. These results are in agreement with reports using other pancreatic cancer cell lines, including PC-2, -3, and -44, PaTu 8988S, HPAF, Capan-2, PaTu 8902, and PaTu-2 cells, which also demonstrated type I collagen adhesion and a 2 integrin subunit expression (Mollenhauer et al, 1987;Weinel et al, 1992).…”

Section: Discussionsupporting

confidence: 61%

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The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

2006

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Pancreatic cancer is characterised by a hallmark desmoplastic response that includes upregulated expression of the extracellular matrix, and type I collagen in particular. Recent studies indicate that pancreatic cancer cells stimulate type I collagen synthesis in adjacent stellate cells, and that this upregulated type I collagen expression promotes the malignant phenotype in tumour cells as defined by increased proliferation, resistance to chemically induced apoptosis, and increased tumorigenesis. The integrin specificity of this interaction between type I collagen and tumour cells was not identified, however. In the present study, we examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration, on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. Our results indicate, for the overwhelming majority of cell lines, that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilising function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, we demonstrate further that the malignant phenotype on type I collagen is mediated specifically by the a 2 b 1 integrin. These results identify a 2 b 1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 61%

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

2006

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“…A previous report showed that recombinant BRCA2 overexpression in the BRCA2-deficient pancreatic adenocarcinoma cell line Capan-1 resulted in substantial decrease in tumorigenicity when inoculated into nude mice (31). More recently, Miyamoto et al (32) observed that Capan-1 cells exhibited an increased proliferation after adhesion to COL4. The mechanisms involved are not yet well understood.…”

Section: Discussionmentioning

confidence: 97%

Up-regulation of Skp2 after Prostate Cancer Cell Adhesion to Basement Membranes Results in BRCA2 Degradation and Cell Proliferation

Moro

Arbini

Marra

et al. 2006

Journal of Biological Chemistry

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Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by ␤ 1 integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its downregulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma. Basement membranes (BM)2 are thin layers of specialized extracellular matrix (ECM) that surround and closely associate with epithelial and endothelial cells, muscle fibers, and nerves. They consist mostly of collagen type IV (COL4) admixed with laminins (LN), nidogens, and the heparan sulfate proteoglycan perlecan (PLN) and may contain small amounts of fibronectin (FN) (1, 2). Although the BM structural role in defining tissue architecture and compartmentalization has long been recognized, its dynamic role in the modulation of cell behavior has only recently been documented (1).Aberrant cancer cell interactions with BM proteins play a crucial role in the biology of metastasis (3). Cancer cells must be able to coordinately decrease cell-cell interactions and increase cell adhesion to an adjacent BM in order to become motile, which along with the capacity of degrading/remodeling a BM directly relates to their metastatic potential (4). This cell behavior is accompanied by changes in the expression and/or usage of various adhesion receptors, including integrins (5). Integrins are transmembrane adhesion receptors for ECM proteins that not only provide physical anchoring cell support but also play a pivotal role in triggering intracellular signaling in response to environmental changes through interactions with molecules ...

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“…Collectively, these changes suggest that EMT occurred in the tumor, during tumor progression and/or in response to sorafenib (45,46). Importantly, EMT correlates with sorafenib resistance and tumor invasiveness (10, 47), whereas the ECM plays a role in drug resistance in a process called "cellular adhesion molecule-dependent drug resistance" (CAM-DR) (48,49). Both processes may have contributed to increased tumor invasiveness and the failure of sorafenib treatment in the patient.…”

Section: Pathway Enrichment Analysis Reveals Potential Mechanisms Ofmentioning

confidence: 99%

Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

Dazert

Colombi

Boldanova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Compensatory signaling pathways in tumors confer resistance to targeted therapy, but the pathways and their mechanisms of activation remain largely unknown. We describe a procedure for quantitative proteomics and phosphoproteomics on snap-frozen biopsies of hepatocellular carcinoma (HCC) and matched nontumor liver tissue. We applied this procedure to monitor signaling pathways in serial biopsies taken from an HCC patient before and during treatment with the multikinase inhibitor sorafenib. At diagnosis, the patient had an advanced HCC. At the time of the second biopsy, abdominal imaging revealed progressive disease despite sorafenib treatment. Sorafenib was confirmed to inhibit MAPK signaling in the tumor, as measured by reduced ribosomal protein S6 kinase phosphorylation. Hierarchical clustering and enrichment analysis revealed pathways broadly implicated in tumor progression and resistance, such as epithelial-to-mesenchymal transition and cell adhesion pathways. Thus, we describe a protocol for quantitative analysis of oncogenic pathways in HCC biopsies and obtained first insights into the effect of sorafenib in vivo. This protocol will allow elucidation of mechanisms of resistance and enable precision medicine.

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Tumor-Stroma Interaction of Human Pancreatic Cancer: Acquired Resistance to Anticancer Drugs and Proliferation Regulation Is Dependent on Extracellular Matrix Proteins

Cited by 211 publications

References 23 publications

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

Up-regulation of Skp2 after Prostate Cancer Cell Adhesion to Basement Membranes Results in BRCA2 Degradation and Cell Proliferation

Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

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