Tumor Cell-extracellular Matrix Interactions Research Articles

Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5h to ∼1.5h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.

Noncanonical Wnt/Ror2 signaling regulates cell-matrix adhesion to prompt directional tumor cell invasion in breast cancer.

Cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic spread during metastasis remains elusive. We demonstrate that the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling and invasion in breast cancer. Ror2 loss-of-function (LOF) triggers the disruption of E-cadherin within tumor cells, accompanied by an increase in tumor cell invasion and collagen realignment in three-dimensional cultures. RNA sequencing of Ror2-deficient organoids further uncovered alterations in actin cytoskeleton, cell adhesion, and collagen cross-linking gene expression programs. Spatially, we pinpoint the up-regulation and redistribution of α5 and β3 integrins together with the production of fibronectin in areas of invasion downstream of Ror2 loss. Wnt/β-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of tumor cell-driven ECM exchanges during cancer invasion and metastasis.

Tumor cell-extracellular matrix interaction: a novel targeted therapeutic approaches in neuroblastoma

Tumor cell-extracellular matrix interaction: a novel targeted therapeutic approaches in neuroblastoma

Rapid fabrication of collagen bundles mimicking tumor-associated collagen architectures

Stromal collagen is upregulated surrounding a solid tumor and presents as dense, thick, linearized, and aligned bundles. The collagen bundles are continually remodeled during tumor progression, and their orientation with respect to the tumor boundary has been correlated with invasive state. Currently, reconstituted-collagen gels are the standard in vitro tumor cell-extracellular matrix interaction model. The reticular, dense, and isotropic nanofiber (~900 nm-diameter, on average) gels do not, however, recapitulate the in vivo structural features of collagen bundling and alignment. Here, we present a rapid and simple method to fabricate bundles of collagen type I, whose average thickness may be varied between about 4 μm and 9 μm dependent upon diluent temperature and ionic strength. The durability and versatility of the collagen bundles was demonstrated with their incorporation into two in vitro models where the thickness and alignment of the collagen bundles resembled various in vivo arrangements. First, collagen bundles aligned by a microfluidic device elicited cancer cell contact guidance and enhanced their directional migration. Second, the presence of the collagen bundles in a bio-inert agarose hydrogel was shown to provide a route for cancer cell outgrowth. The unique structural features of the collagen bundles advance the physiological relevance of in vitro collagen-based tumor models for accurately capturing tumor cell-extracellular matrix interactions. Statement of significanceCollagen in the tumor microenvironment is upregulated and remodeled into dense, thick, and aligned bundles that are associated with invasive state. Current collagen-based in vitro models are based on reticular, isotropic nanofiber gels that do not fully recapitulate in vivo tumor stromal collagen. We present a simple and robust method of rapidly fabricating cell-scale collagen bundles that better mimic the remodeled collagen surrounding a tumor. Interacting with the bundles, cancer cells exhibited drastically different phenotypic behaviors, compared to nanofiber scaffolds. This work reveals the importance of microscale architecture of in vitro tumor models. The collagen bundles provide physiologically relevant collagen morphologies that may be easily incorporated into existing models of tumor cell-extracellular matrix interactions.

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide invivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.

Tumor Cell-Extracellular Matrix Interaction Modulates MMP-1 in Breast Cancer

Increased MMP-1 expression in various tumor cells is significantly correlated with cancer progression. Enhanced secreted and intracellular level of MMP-1 is found in breast cancer cell line MDA-MB-231 in presence of ECM glycoprotein fibronectin. To extrapolate this study into in vivo system, we observed the expression of MMP-1, fibronectin and α5β1 integrin, which is the receptor for fibronectin, in breast cancer tissue samples. Expression of active form of MMP-1 was increased in tumor samples compared with the non-tumor counterpart. In some samples pro-MMP-1 was decreased but active form was increased in tumor part. The difference was more prominent in advanced stage tumor. ELISA showed appreciable increase in expression of α5 and β1integrins in tumor tissue in comparison to the non tumor counterpart in case of advanced stage tumor. Though there is no appreciable difference in fibronectin concentration, enhanced α5, β1 integrin expression may mediate enhanced cell-ECM interaction to upregulate MMP-1 in tumor samples compared with the matched control.

SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage

Fibrosis results from inflammatory tissue damage and impaired regeneration. In the context of bleomycin-induced pulmonary fibrosis, we demonstrated that the matricellular protein termed secreted protein acidic and rich in cysteine (SPARC) distinctly regulates inflammation and collagen deposition, depending on its cellular origin. Reciprocal Sparc(-/-) and wild-type (WT) bone marrow chimeras revealed that SPARC expression in host fibroblasts is required and sufficient to induce collagen fibrosis in a proper inflammatory environment. Accordingly, Sparc(-/-) >WT chimeras showed exacerbated inflammation and fibrosis due to the inability of Sparc(-/-) macrophages to down-regulate tumor necrosis factor production because of impaired responses to tumor growth factor-β. Hence, the use of bone marrow cells expressing a dominant-negative form of tumor growth factor-β receptor type II under the monocyte-specific CD68 promoter, as a decoy, phenocopied Sparc(-/-) donor chimeras. Our results point to an unexpected dual role of SPARC in oppositely influencing the outcome of fibrosis.

Involvement of ecto-5′-nucleotidase/CD73 in U138MG glioma cell adhesion

Glioblastoma multiform is the most common and aggressive type of brain tumor. The overexpression of ecto-5'-nucleotidase/CD73 (ecto-5'-NT/CD73), an adhesion molecule and the main enzymatic source of extracellular adenosine, has been reported in tumor cells, and it is emerging as a component of glioma progression. Here, we evaluated the involvement of ecto-5'-NT/CD73 in cell adhesion through its interaction with different components of the extracellular matrix in the human U138MG glioma cell line. The results indicated that adenosine induced an increase in glioma cell adhesion. The treatment of glioma cells with adenosine receptor antagonists, APCP (α,β-methylene ADP) and dipyridamole prevented the adenosine effect, indicating the participation of extracellular and intracellular signaling pathways in cell adhesion mediated by adenosine. The ECM protein laminin (lam) and chondroitin sulfate (ChS) modulated the ecto-5'-NT/CD73 activity and glioma adhesion in a parallel manner, suggesting the involvement of purinergic signaling in the effects mediated by the extracellular matrix. Taken together, these results suggest that ecto-5'-NT/CD73, an important producer of extracellular adenosine, may modulate glioma cell adhesion and tumor cell-extracellular matrix interactions.

Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis

Other than genetic imprinting and epithelial to mesenchymal transition, cancer cells need interaction with the nearby stroma toward metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) deposition and cell-ECM interaction. Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through alpha(v)beta(5) integrin. Indeed, RNA interference knockdown of beta(5) integrin expression reduces cell migration in vitro and metastasis in vivo. Together these results show that macrophage-derived SPARC takes part in metastasis, acting at the step of integrin-mediated migration of invasive cells.

MUC4 Mucin Potentiates Pancreatic Tumor Cell Proliferation, Survival, and Invasive Properties and Interferes with Its Interaction to Extracellular Matrix Proteins

MUC4, a transmembrane mucin, is aberrantly expressed in pancreatic adenocarcinomas while remaining undetectable in the normal pancreas. Recent studies have shown that the expression of MUC4 is associated with the progression of pancreatic cancer and is inversely correlated with the prognosis of pancreatic cancer patients. In the present study, we have examined the phenotypic and molecular consequences of MUC4 silencing with an aim of establishing the mechanistic basis for its observed role in the pathogenesis of pancreatic cancer. The silencing of MUC4 expression was achieved by stable expression of a MUC4-specific short hairpin RNA in CD18/HPAF, a highly metastatic pancreatic adenocarcinoma cell line. A significant decrease in MUC4 expression was detected in MUC4-knockdown (CD18/HPAF-siMUC4) cells compared with the parental and scrambled short interfering RNA-transfected (CD18/HPAF-Scr) control cells by immunoblot analysis and immunofluorescence confocal microscopy. Consistent with our previous observation, inhibition of MUC4 expression restrained the pancreatic tumor cell growth and metastasis as shown in an orthotopic mouse model. Our in vitro studies revealed that MUC4-associated increase in tumor cell growth resulted from both the enhanced proliferation and reduced cell death. Furthermore, MUC4 expression was also associated with significantly increased invasiveness (P < or = 0.05) and changes in actin organization. The presence of MUC4 on the cell surface was shown to interfere with the tumor cell-extracellular matrix interactions, in part, by inhibiting the integrin-mediated cell adhesion. An altered expression of growth- and metastasis-associated genes (LI-cadherin, CEACAM6, RAC1, AnnexinA1, thrombomodulin, epiregulin, S100A4, TP53, TP53BP, caspase-2, caspase-3, caspase-7, plakoglobin, and neuregulin-2) was also observed as a consequence of the silencing of MUC4. In conclusion, our study provides experimental evidence that supports the functional significance of MUC4 in pancreatic cancer progression and indicates a novel role for MUC4 in cancer cell signaling.

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB dependent activation of the urokinase plasminogen activator system

Introduction: The mechanisms of bacterial lipopolysaccaride (LPS) induced accelerated metastatic tumor growth in murine models are poorly understood. The urokinase plasminogen activator system, comprising urokinase plasminogen activator (u-PA), urokinase plasminogen activator receptor (u-PAR) and plasminogen activator inhibitor 1 (PAI-1), is intimately implicated in tumor cell extracellular matrix interactions fundamental to tumour cell invasion. The aim of this study was determine if LPS directly promotes tumor cell extracellular matrix adhesion and invasion through activation of the urokinase plasminogen activator system and elucidate the pathways involved in this process. Methods: ELISA was used to assess cellular and supernatant u-PA, u-PAR, PAI-1 levels in sw480 and sw620 colorectal cancer cell lines following stimulation with LPS (100 ng/ml, 1000 ng/ml and 10,000 ng/ml) for different time periods (0, 6, 12 18 and 24 hours). Activated u-PA, TLR-4, Iκ-Bα and phospho- Iκ-Bα were evaluated by western blot analysis and u-PA activity by chromogenic assay. Surface u-PAR and TLR-4 expression were examined by FACS analysis, vitronectin adhesion by fluorgenic adhesion assay and in-vitro invasion by ECmatrix invasion chambers. Results: LPS stimulation upregulates u-PA and u-PAR in a dose and time dependent manner. Stimulation of sw480 and sw620 cancer cells with 100ng/ml LPS for 18 hours augmented cell supernatant u-PA concentration and activity by 50% and 32% respectively (*;p>0.01 compared to baseline). This translated into a 27% increase in tumor cell vitronectin adhesion and a 34% increase in in-vitro ECmatrix invasion above baseline (Table 1) (**,p<0.05). Such effects were ameliorated by u-PA and u-PAR inhibition utilising u-PAR and u-PA blocking antibodies and by the novel u-PA inhibitor wxc-340 (*,p>0.01, **,p>0.05;compared to LPS stimulated cells). Inhibition of NF-κB and TLR-4 significantly impairs LPS mediated activation of the u-PA system, tumor cell vitronectin adhesion and in vitro invasion (Table 1) (*,p<0.01, **,p>0.05 compared to LPS stimulated cells). Conclusions: This study demonstrates that LPS promotes tumour cell extracellular matrix adhesion and in vitro invasion through activation of the urokinase plasminogen activator system in a TLR-4 and NF-κB dependent manner.

Treatment of malignancy by activation of the plasminogen system.

The blood coagulation mechanism in general and the plasminogen system in particular contribute to malignant growth and dissemination in complex ways. This article reviews the extensive literature that has accumulated over the past half-century on effects of plasminogen activation on the natural history of experimental animal and human malignancy. Although the potent enzymes generated upon plasminogen activation may have a direct effect on tumor cells, it is more likely that their mechanism of action is related to disruption of the tumor cell-extracellular matrix interaction. These observations suggest novel approaches to the experimental therapy of cancer.

Molecular pathology of tumor metastasis. I. Predictive pathology.

Millennium reviews of oncology agreed that the last century produced major developments mainly in the management of the primary tumor, but despite all of these results, cancer still remains among the leading causes of death due to the failure of clinical management of disseminated disease. This failure is primarily due to the lack of detailed information on the molecular mechanisms of tumor metastasis. Therefore, one of the hottest fields in experimental oncology is metastasis research, which provides more and more information about the molecular mechanisms. However, this information is fragmented and is not yet exploited in clinical practice. A new field of diagnostic pathology recently emerged, which translates basic research data to diagnostic practice to provide clinically relevant information on the biological potential (in this case metastatic potential) of the malignant tumors. Since tumor cell-extracellular matrix interactions are key features of tumor dissemination, expression of genes responsible for them can define the metastatic potential of malignant tumors. This review summarizes our recent knowledge on the metastatic geno- and phenotype of major human solid tumors: lung, colon, breast, prostate cancers and malignant melanoma.

Establishment of human prostate carcinoma skeletal metastasis models

BACKGROUND. Prostate carcinoma progression from an androgen dependent (AD) state to an androgen independent (Al) state occurs clinically in patients who undergo hormonal therapy. In their laboratory, the authors developed two human prostate carcinoma skeletal metastasis models, the LNCaP progression model and the ARCaP model, to investigate phenotypic and genotypic changes of prostate carcinoma cells during disease progression and to understand molecular pathways for potential therapeutic targeting. METHODS. LNCaP or ARCaP cells were inoculated in athymic mice and were exposed to selective hormonal conditions both in vivo and in vitro. The effects of various hormonal treatment regimens on tumor volumes and distant metastasis and the effects of bone stromal cells on prostate specific antigen (PSA) expression by prostate carcinoma cells were evaluated. RESULTS. The authors propose that prostate carcinoma progression from the AD state to the Al state assumes three AI phenotypes: AI that remains androgen responsive, AI that is unresponsive to androgen stimulation, and AI that is suppressed by or hypersensitive to androgen. AI prostate carcinoma cells interacted reciprocally with osteoblasts to produce enhanced tumor growth and osteoblastic reaction when they are deposited in bone. Bone stromal cell conditioned media stimulated prostate carcinoma cell growth and suppressed its PSA expression, as also evidenced by androgen receptor-mediated transactivation of PSA promoter reporter activity. Conditioned media obtained from prostate carcinoma cells also stimulated osteoblastic cell growth in vitro. A novel gene therapy strategy is being developed to target prostatic tumor epithelium and its supporting stroma using tissue specific and tumor-restricted, promoter-directed toxic gene expression in both cellular compartments. In addition, new strategies are being designed to target the tumor endothelial system in the stroma and tumor cell-extracellular matrix interaction mediated by isotype specific integrins. CONCLUSIONS. Prostate carcinoma skeletal metastasis models may prove useful in developing a new targeting strategy for the prevention and treatment of patients with prostate carcinoma.

Establishment of human prostate carcinoma skeletal metastasis models.

Prostate carcinoma progression from an androgen dependent (AD) state to an androgen independent (AI) state occurs clinically in patients who undergo hormonal therapy. In their laboratory, the authors developed two human prostate carcinoma skeletal metastasis models, the LNCaP progression model and the ARCaP model, to investigate phenotypic and genotypic changes of prostate carcinoma cells during disease progression and to understand molecular pathways for potential therapeutic targeting. LNCaP or ARCaP cells were inoculated in athymic mice and were exposed to selective hormonal conditions both in vivo and in vitro. The effects of various hormonal treatment regimens on tumor volumes and distant metastasis and the effects of bone stromal cells on prostate specific antigen (PSA) expression by prostate carcinoma cells were evaluated. The authors propose that prostate carcinoma progression from the AD state to the AI state assumes three AI phenotypes: AI that remains androgen responsive, AI that is unresponsive to androgen stimulation, and AI that is suppressed by or hypersensitive to androgen. AI prostate carcinoma cells interacted reciprocally with osteoblasts to produce enhanced tumor growth and osteoblastic reaction when they are deposited in bone. Bone stromal cell conditioned media stimulated prostate carcinoma cell growth and suppressed its PSA expression, as also evidenced by androgen receptor-mediated transactivation of PSA promoter reporter activity. Conditioned media obtained from prostate carcinoma cells also stimulated osteoblastic cell growth in vitro. A novel gene therapy strategy is being developed to target prostatic tumor epithelium and its supporting stroma using tissue specific and tumor-restricted, promoter-directed toxic gene expression in both cellular compartments. In addition, new strategies are being designed to target the tumor endothelial system in the stroma and tumor cell-extracellular matrix interaction mediated by isotype specific integrins. Prostate carcinoma skeletal metastasis models may prove useful in developing a new targeting strategy for the prevention and treatment of patients with prostate carcinoma.

Type I collagen metabolites as tumor markers in patients with lung carcinoma

BACKGROUND Components of the extracellular matrix play a fundamental role in the process of tumor invasion. The objective of this study was to evaluate the value of Type I collagen metabolites as tumor markers in patients with lung carcinoma. METHODS In this study, the serum concentrations of the cross-linked carboxyterminal telopeptide of Type I collagen (ICTP) and the aminoterminal propeptide of Type I collagen (PINP) were measured in 59 consecutive patients with lung carcinoma. The blood concentrations of neuron-specific enolase (NSE), carcinoembryogenic antigen (CEA), sialyl Le-1 antigen (SLX), squamous cell carcinoma antigen (SCC), and D-dimer were also evaluated. Data obtained on 18 age-matched healthy subjects and 12 age-matched patients with benign lung disease were available for comparison. RESULTS The serum concentrations of PINP were significantly higher in patients with lung carcinoma than in age-matched controls. Prechemotherapy values of PINP and ICTP were significantly increased in patients who did not respond to chemotherapy compared with those who did respond. PINP and ICTP were significantly correlated with clinical stage, extent of bone metastasis, survival time, and D-dimer. PINP was also significantly correlated with tumor size. ICTP was significantly correlated with CEA, SLX, SCC, and NSE. PINP also tended to correlate with these tumor-associated glycoproteins. PINP had a better receiver operating characteristic curve than ICTP. The specificity of PINP (79%) for the diagnosis of bone metastasis was superior to that of ICTP (58%). CONCLUSIONS The results of this study showed that, in addition to the important information that ICTP and PINP provide about the tumor cell–extracellular matrix interaction, they appear to be of great value as adjunct tools for the diagnosis of bone metastasis and as markers of the clinical response to therapy, clinical progression, and prognosis in lung carcinoma patients. However, more studies must be conducted to evaluate further the utility of these markers before their application in clinical practice. Cancer 1999;85:1951–7. © 1999 American Cancer Society.

Type I collagen metabolites as tumor markers in patients with lung carcinoma

BACKGROUND Components of the extracellular matrix play a fundamental role in the process of tumor invasion. The objective of this study was to evaluate the value of Type I collagen metabolites as tumor markers in patients with lung carcinoma. METHODS In this study, the serum concentrations of the cross-linked carboxyterminal telopeptide of Type I collagen (ICTP) and the aminoterminal propeptide of Type I collagen (PINP) were measured in 59 consecutive patients with lung carcinoma. The blood concentrations of neuron-specific enolase (NSE), carcinoembryogenic antigen (CEA), sialyl Le-1 antigen (SLX), squamous cell carcinoma antigen (SCC), and D-dimer were also evaluated. Data obtained on 18 age-matched healthy subjects and 12 age-matched patients with benign lung disease were available for comparison. RESULTS The serum concentrations of PINP were significantly higher in patients with lung carcinoma than in age-matched controls. Prechemotherapy values of PINP and ICTP were significantly increased in patients who did not respond to chemotherapy compared with those who did respond. PINP and ICTP were significantly correlated with clinical stage, extent of bone metastasis, survival time, and D-dimer. PINP was also significantly correlated with tumor size. ICTP was significantly correlated with CEA, SLX, SCC, and NSE. PINP also tended to correlate with these tumor-associated glycoproteins. PINP had a better receiver operating characteristic curve than ICTP. The specificity of PINP (79%) for the diagnosis of bone metastasis was superior to that of ICTP (58%). CONCLUSIONS The results of this study showed that, in addition to the important information that ICTP and PINP provide about the tumor cell–extracellular matrix interaction, they appear to be of great value as adjunct tools for the diagnosis of bone metastasis and as markers of the clinical response to therapy, clinical progression, and prognosis in lung carcinoma patients. However, more studies must be conducted to evaluate further the utility of these markers before their application in clinical practice. Cancer 1999;85:1951–7. © 1999 American Cancer Society.

Type I collagen metabolites as tumor markers in patients with lung carcinoma

Components of the extracellular matrix play a fundamental role in the process of tumor invasion. The objective of this study was to evaluate the value of Type I collagen metabolites as tumor markers in patients with lung carcinoma. In this study, the serum concentrations of the cross-linked carboxyterminal telopeptide of Type I collagen (ICTP) and the aminoterminal propeptide of Type I collagen (PINP) were measured in 59 consecutive patients with lung carcinoma. The blood concentrations of neuron-specific enolase (NSE), carcinoembryogenic antigen (CEA), sialyl Le-1 antigen (SLX), squamous cell carcinoma antigen (SCC), and D-dimer were also evaluated. Data obtained on 18 age-matched healthy subjects and 12 age-matched patients with benign lung disease were available for comparison. The serum concentrations of PINP were significantly higher in patients with lung carcinoma than in age-matched controls. Prechemotherapy values of PINP and ICTP were significantly increased in patients who did not respond to chemotherapy compared with those who did respond. PINP and ICTP were significantly correlated with clinical stage, extent of bone metastasis, survival time, and D-dimer. PINP was also significantly correlated with tumor size. ICTP was significantly correlated with CEA, SLX, SCC, and NSE. PINP also tended to correlate with these tumor-associated glycoproteins. PINP had a better receiver operating characteristic curve than ICTP. The specificity of PINP (79%) for the diagnosis of bone metastasis was superior to that of ICTP (58%). The results of this study showed that, in addition to the important information that ICTP and PINP provide about the tumor cell-extracellular matrix interaction, they appear to be of great value as adjunct tools for the diagnosis of bone metastasis and as markers of the clinical response to therapy, clinical progression, and prognosis in lung carcinoma patients. However, more studies must be conducted to evaluate further the utility of these markers before their application in clinical practice.

Epithelial-stromal interactions in colon cancer.

In this paper investigations concerning the interactions at the interface between tumor cells and tumor stroma are reviewed. As a model for tumor cell-extracellular matrix interaction human colorectal carcinoma cell lines, in vitro and in vivo, in nude mouse xenografts, were chosen. Based on the available data and on a review of the literature the following conclusions can be drawn. Most malignant epithelial neoplasms at the site of tumor cell invasion display defects in the epithelial basement membrane. This is not merely the result of enzymatic dissolution but rather reflects a shift in basement membrane turnover towards degradation. Elsewhere in the same primary tumor or in a metastasis the balance might be shifted more towards basement membrane deposition. The tendency of a tumor to deposit basement membranes reflects the biological potential of the neoplasm. Basement membranes are deposited by stromal cells or by a concerted action of tumor and stromal cells. Differentiation in a carcinoma is modulated by factors in the extracellular matrix. Endocrine differentiation can be induced in vitro by native basement membranes but also by direct contact of the tumor cells with fibroblasts. Basic FGF is one of the extracellular matrix factors with differentiation inducing capacity. Expression of cell adhesion molecules and integrin receptors tends to be down-regulated in carcinoma cells. Alterations in the expression of these proteins might not be constitutive but rather modulated by the direct environment of the tumor cell and might not only include quantitative alterations but also changes in their cell surface distribution, causing or following loss of cell polarity.