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Expression de protéines de la matrice osseuse dans les cancers mammaires humains : rôles potentiels dans la formation de microcalcifications et dans la genèse de métastases osseuses


Bulletin du Cancer. Volume 84, Numéro 1, 17-24, Janvier 1997, Articles originaux


Résumé   Summary  

Auteur(s) : Akeila Bellahcène, Vincent Castronovo, Metastasis Research Laboratory, University of Liège, Bât. B23, Sart-Tilman, B-4000 Liège, Belgium..

Résumé : Le squelette est la cible privilégiée des cellules métastatiques cancéreuses mammaires humaines. En effet, la majorité des patients présentant un cancer du sein à un stade avancé développent des métastases osseuses responsables d’une morbidité importante. L’ostéotropisme fréquent des cellules cancéreuses mammaires suggère qu’elles possèdent une affinité particulière pour le tissu minéralisé. L’observation que les cellules cancéreuses mammaires sont capables d’induire la formation de microcalcifications au niveau de la tumeur primaire suggère qu’elles peuvent créer un microenvironnement favorable au dépôt d’hydroxyapatite comparable à celui retrouvé au niveau du tissu osseux. L’ostéonectine (OSN), l’ostéopontine (OPN) et la sialoprotéine osseuse (BSP), 3 protéines de la matrice osseuse, sont exprimées dans les cancers mammaires humains. La BSP, une phosphoprotéine comprenant une séquence RGD (Arg-Gly-Asp), joue un rôle important lors de la formation des cristaux d’hydroxyapatite mais aussi au moment de leur résorption en médiant l’attachement des ostéoclastes à la matrice extracellulaire osseuse. La détection de BSP, au niveau protéine et ARNm, dans les tumeurs mammaires et dans 3 lignées cellulaires cancéreuses mammaires (MCF-7, T47-D et MDA- MB-231) indique que les cellules cancéreuses mammaires sont capables de synthétiser cette protéine de la matrice osseuse. Il est intéressant de noter que l’expression de BSP au niveau de la tumeur primaire est corrélée au développement de métastases osseuses et qu’elle est un facteur de mauvais pronostic pour la patiente. Ces résultats suggèrent que l’expression ectopique de protéines de la matrice osseuse pourrait être impliquée dans l’acquisition d’un phénotype ostéotropique par les cellules cancéreuses mammaires métastatiques. Ces observations ouvrent de nouvelles perspectives pour la compréhension des mécanismes moléculaires impliqués dans la formation de métastases osseuses.

Mots-clés : protéines de la matrice osseuse, cancer du sein, métastases osseuses, sialopro-téine osseuse.

Illustrations

ARTICLE

Breast cancer is a major cause of cancer mortality in women between 35 and 45 years in Western countries. Morbidity and mortality in these patients are associated to the development of distant metastases. Metastatic breast cancer cells are characterized by a high osteotropism. Bone is indeed their most preferred organ for secondary implantation and colonization. Autopsies performed on advanced breast cancer patients revealed that they all suffer from osteolytic metastases. Osseous metastases can generate pain, pathological fractures, and abnormalities in calcium metabolism and bone marrow replacement may also occur (Body, 1992). Cancer cell osteotropism is not a general feature of malignant cells but is restricted to a few type of cancers including prostate, thyroid, lung carcinoma as well as neuroblastoma and myeloma (Walther, 1948). Beside the properties that metastatic cells must possess to successfully achieve the steps of the metastatic cascade (Fidler, 1990; Yoneda et al., 1994), osteotropic breast cancer cells must exhibit certain features that facilitate their selective affinity for the skeleton. The major component of bone consists of hard mineralized tissue and cancer cells metastasizing to this tissue need to have the capacity to destroy bone in order to progress. Indeed, it has been shown that breast cancer cells can induce a direct stimulation of bone resorption in vitro (Eilon and Mundy, 1978). It has also been demonstrated that breast cancer cells are able to activate osteoclast cells (Galasko and Bennett, 1976; Galasko, 1976). Interestingly, parathyroid hormone-related protein (PTH-rP) which is a powerful stimulator of bone resorption has been localized in breast cancer metastases (Powell et al., 1991; Southby et al., 1990). Moreover, evidence that PTH-rP may contribute to the ability of breast cancer cells to grow as bone metastases is given by another study which demonstrates that the level of PTH-rP mRNA expression is significantly higher in breast malignant tumors from patients who later developed bone metastases compared to patients who had no recurrences or metastases and patients who developed soft-tissue metastases (Bouizar et al., 1993).

Next to the known propensity for breast cancer cells to metastasize to bone, another clinical observation suggesting the existence of a privileged relations between breast and bone tissue is that deposits of calcium compounds are often seen among breast carcinoma cells. Ectopic calcifications associated with breast malignant lesions are generally formed by hydroxyapatite which is also the basic mineral found in the skeleton. Attempts to differentiate benign and malignant calcifications by chemical analysis have been unsuccessful. However, according to their structure and chemical composition, 2 principal types of microcalcifications can be distinguished: type I microcalcifications are composed of calcium oxalate, they often result of secretory processes in benign breast disease and are rarely associated with malignancy. Type II microcalcifications consist in calcium phosphate crystals, essentially hydroxyapatite. Since they are stained by hematoxylin, these type II microcalcifications can be easily detected and they have been reported in patients with either benign or malignant breast lesions (Frappart et al., 1984). However, these microcalcifications are not always observed in the histologic specimen because they can be removed by the microtome blade during preparation of the tissue. In fact, mammography is the only technique capable of depicting calcifications within the breast. Although mammographically detected microcalcifications are frequently the only sign of a malignant breast disease, the mechanism of their deposition has not yet been elucidated. The observation that hydroxyapatite crystals are found in association with breast cancer cells suggest that these latter are able to generate within their neighbourhood a microenvironment that favour the crystallization of calcium and phosphate into the bone specific mineral.

Bone, dentine and mineralized tendon have, at the molecular level, similar structures derived from the organized growth of hydroxyapatite crystals within a matrix of type I collagen fibrils and other organic components. The osteoid bone matrix is primarily produced by osteoblasts and subsequently becomes calcified to form the mineralized matrix. After proper stimulation, the osteoclasts are capable of dissolving the matrix. Processes of both bone production and degradation go on continuously and the actual state of the bone depends on the balance between these 2 processes. The most abundant protein of the bone matrix is type I collagen (90% of the organic phase), but the noncollagenous proteins produced primarily by cells in the osteoblastic lineage are now drawing much attention. Among the bone matrix proteins listed in table I, osteonectin (OSN), osteopontin (OPN) and bone sialoprotein (BSP) have been extensively studied because they are involved in the onset of bone matrix mineralization (for review see Young et al., 1993). OSN is a 32 kDa protein named based on its ability to bind to calcium, hydroxyapatite and type I collagen and its localization in mineralized tissues (bone and dentine) (Termine et al., 1981a; 1981b). The cloning of OSN cDNA and subsequent protein sequencing allowed to localize OSN in mineralized but also in many nonmineralized tissues. OSN appears to be identical to a protein produced by parietal endoderm cells known as SPARC (Secreted Protein Acidic and Rich in Cystein) (Mason et al., 1986) and to BM-40 protein that was extracted from Epstein-Holm-Swarm (EHS) tumor (Dziadek et al., 1986). SPARC/OSN is also secreted by platelets (Stenner et al., 1986). OSN has been also found to be identical to a 43 kDa "culture shock" protein produced by bovine endothelial cells after repeated passages (Sage et al., 1989). The distribution of OSN suggests that it serves multiple functions, although its precise functions are poorly understood. Several studies in vitro have demonstrated that OSN is involved in cell proliferation and migration, "culture shock" and mineralization of bone tissue (for review see Tracy et al., 1988).

OPN is a 44 kDa glycoprotein expressed prominently in bone (Chen et al., 1993; Yoon et al., 1987) and at the apical surface of lining epithelial cells (Brown et al., 1992). OPN is produced by various normal tissues, including kidney, inner ear, uterus, and decidual metrial gland (Nomura et al., 1988). It has also been identified in human milk (Senger et al., 1989). The cDNA-predicted amino acid sequence of OPN contains the Arg-Gly-Asp (RGD) motif (Oldberg et al., 1986) which is found in fibronectin and other cell adhesion proteins, and was shown to interact with cell surface receptors of the integrin family (Pytela et al., 1986). OPN promoted the attachment of rat osteosarcoma cells and human gingiva fibroblasts to plastic dishes, a phenomenon that was inhibited by RGD-containing peptides (Oldberg et al., 1986; Somerman et al., 1987). The precise function of OPN in bone is still unknown, although it may mediate the attachment and spreading of osteblasts and osteoclasts (Reinholt et al., 1990), and its phosphorylation and sulfation may play a role in biomineralization (Glimcher, 1989). A variety of independent observations have suggested that OPN expression may be altered in cancer. OPN is dramatically upregulated upon transformation of cells (Craig et al., 1988; 1989). Northern analysis demonstrated markedly increased concentrations of OPN mRNA in all human carcinoma studied (breast, lung, colon, stomach, endometrium and thyroid) when compared with corresponding normal tissues (Brown et al., 1994). Because of its RGD motif, OPN has an adhesive function which could be important in mediating interactions between tumor cells and extracellular matrix during invasion and metastasis. Moreover, increased levels of OPN have been detected in the serum of patients with metastatic carcinoma compared to the normal circulating levels (Senger et al., 1988). It has been shown that 1,25-dihydroxyvitamin D3 increases the level of OPN mRNA, whereas dexamethasone reduces the steady-state level of OPN mRNA (Yoon et al., 1987).

OPN shares its calcium binding properties and hydroxyapatite affinity with another sialoprotein of bone: BSP, also known as bone sialoprotein II. BSP is a highly post-translationally modified protein (40-50% carbohydrate content with 14% sialic acid) that have been identified in human bone (Fisher et al., 1983). BSP contains an RGD cell binding sequence and binds to cells via an integrin, the avb3 vitronectin receptor (Oldberg et al., 1988). Studies on the developmental expression of BSP have shown that BSP mRNA is expressed at high levels at the onset of bone, dentine and cementum formation (Bianco et al., 1991; Chen et al., 1991; 1992) and that BSP localizes to sites of mineral crystal formation (Bianco et al., 1993; Kasugai et al., 1992). In vitro studies have also shown that the deposition of BSP into the extracellular matrix is associated with hydroxyapatite formation (Chen et al., 1994). Moreover, BSP, contrarily to OPN, has been shown to induce the formation of hydroxyapatite in a steady-state agarose gel system (Hunter and Goldberg, 1993). These studies have revealed the key role of BSP in the initiation of mineral crystal formation process. On the other hand, BSP and BSP mRNA were detected in 2 types of multinuclear cells: the placental trophoblasts (Bianco et al., 1991) and the osteoclast cells. Studies have suggested that, in these latter cells, BSP could play a role in matrix erosion. The synthesis of BSP is regulated by steroid hormones. BSP mRNA is increased threefold in calvaria tissue after exposure to dexamethasone for 24 h. This synthetic glucocorticoid has been previously demonstrated to promote the formation of calcified bone nodules by primary cells isolated from rat calvaria (Bellows et al., 1986). In contrast, treatment with Vit D3 which is thought to suppress bone formation by blocking the differentiation of osteoblasts precursors, reduced the amount of BSP mRNA to one third of that in the control without steroid (Oldberg et al., 1989). These effects are the opposite of those noted for OPN mRNA (Yoon et al., 1987).

Expression of bone matrix proteins in human breast cancer

The observation that human breast cancer cells are able to induce hydroxyapatite crystallization and exhibit a high affinity for the skeleton led us to test the hypothesis that malignant mammary cells could express bone matrix proteins that would create the appropriate microenvironment to trigger hydroxyapatite formation and facilitate their interaction with bone matrix (Castronovo and Bellahcène, 1996). In preliminary studies, we therefore examined by immunohistochemistry the expression of OSN, OPN and BSP in a series of human breast cancers (Bellahcène and Castronovo, 1995; Bellahcène et al., 1994). We analyzed the expression of these 3 bone matrix proteins in 79 breast lesions, including 28 benign and 51 malignant specimens.

For BSP, 2 polyclonal antibodies, one directed against intact human BSP (LF-6) and the other against a synthetic peptide of BSP (residues 277-294) (LF-83) were used and gave identical results. Normal mammary glands expressed undetectable or barely detectable amounts of BSP (figure 1A). The majority of the benign lesions examined were generally unstained (0) or weakly stained (1+). Most of the breast carcinoma specimens (around 87%) showed a significant increase (p = 0.0001) in BSP expression. Breast carcinomas with microcalcifications were the ones with highest immunoreactivity (2+ or 3+) to BSP antibodies (figure 1B). Expression of BSP in breast cancer lesions was often heterogeneous. Interestingly, breast cancer cells with the more invasive phenotype (isolated infiltrating malignant cells) were strongly positive (figure 1C). A significant increase in BSP expression was noted in the invasive portion of in situ breast carcinoma (figure 1D) (Bellahcène et al., 1994).

For OPN and OSN, we found that normal mammary tissue associated with the lesions examined expressed generally undetectable or lightly detectable (0 or 1+) amounts. Benign breast lesions, including fibroadenoma and fibrocystic dysplasia, were generally weakly stained (0 or 1+) with both anti-OSN and anti-OPN antibodies (96.4 and 60.7%, respectively). Interestingly, the majority of both in situ and invasive breast carcinoma lesions showed a strong expression (2+ or 3+) for OSN or OPN (74.5 and 84.3%, respectively) (figure 2, A and B) (Bellahcène and Castronovo, 1995). As observed for BSP, high expression of these 2 bone matrix proteins was associated with frequent microcalcifications deposition in the lesion.

While the detection of OSN and OPN in breast malignant tissues was not surprising based on previous reports, the observation that BSP was expressed by human breast cancer cells was unexpected. Indeed, previous BSP mRNA and protein distribution studies showed that BSP was mainly restricted to mineralized tissues.

Expression of BSP in human breast cancer cell lines

The detection of BSP in human breast cancer lesions raises questions about its potential role(s) during breast cancer progression. Because BSP is secreted and is present in the serum (Chenu and Delmas, 1992), the positivity of breast cancer cells for BSP could have been due to an uptake of the circulating phosphoprotein by the cells rather than to an intrinsic expression. It was therefore important to demonstrate BSP mRNA in human breast cancer cells. Furthermore, in order to study the molecular mechanisms involved in the ectopic expression of BSP, it was important to identify human breast cancer cells that expressed the bone matrix protein. We were able to demonstrate BSP expression at both protein and mRNA levels in 3 human breast cancer cell lines: MCF-7, T47-D and MDA-MB-231, as well as in human breast cancer tissue (Bellahcène et al., 1996a). Using a specific polyclonal anti-BSP antibody, we have shown by both FACS analysis and immunocytochemistry experiments (figure 3A), that all human breast cancer cell lines studied express BSP. This phosphoprotein was localized at the cell surface and in the cytosol of the estrogen receptor (ER) positive MCF-7 and T47-D cell lines while it was detected only in the cytosol of the ER negative MDA-MB-231 cells. Using LF-83 polyclonal anti-BSP antibody, we were able to identify by immunoblot a ~ 97 kDa band on total protein extracts from the 3 cell lines. RT-PCR reactions using specific oligonucleotides performed on total RNA of MCF-7, T47-D and MDA-MB-231 cell lines demonstrated the presence of BSP mRNA. Interestingly, we found that only a subpopulation of ER positive breast cancer cells express BSP on their surface. ER negative MDA-MB-231 cells did not exhibit cell surface immunoreactivity to anti-BSP antibody. This observation could be of relevance since, in vivo, the osteotropic phenotype of breast adenocarcinoma is significantly associated with the ER status. In fact, ER positive malignant tumors metastasize with a higher incidence to bone than ER negative breast cancers (Coleman and Rubens, 1987). MCF-7, T47-D and MDA-MB-231 breast cancer cell lines will prove to be useful models for the evaluation of the mechanisms involved in the osteotropism of mammary cancer cells. As mentioned above, BSP expression is modulated by steroids in osteogenic cells. The possibility that BSP synthesis in breast cancer cells is also regulated by steroid hormones is currently under investigation. The effects of other substances such as parathyroid hormone (PTH) and cytokines on the expression of BSP should be also clarified. PTH modulates the production of many extracellular matrix proteins in osteoblastic cells. Interestingly, target cells of PTH correspond to OPN-producing cells which include not only osteoblasts (Rodan and Rodan, 1984) but also proximal tubule, distal tubule and ascending loop of Henle cells. Human PTH has been shown to significantly decrease the amount of OPN protein and mRNA in the rat osteosarcoma cell line, ROS 17/2.8 (Noda and Rodan, 1989). These results suggest that OPN expression would be reduced by PTH as part of its known catabolic effects on bone.

Expression of BSP in human breast cancer and prognosis

Our finding that ectopic expression of BSP in primary breast cancer was a frequent phenomenon led us to test the hypothesis that detection of BSP in primary human breast cancer could be a potential indicator of the ability of breast cancer cells to metastasize to bone. In a preliminary study, BSP expression was evaluated in the primary breast cancer of 39 patients using immunoperoxidase and 2 specific anti-BSP antibodies (Bellahcène et al., 1996b). None of these patients presented clinically or scintigraphically detectable bone metastases at the time of surgery. In the course of their disease, 22 patients developed clinically diagnosed bone metastases. Expression of BSP in breast cancer cells from patients who developed bone metastases was significantly higher (p = 0.008, according to the Mann-Withney test) than in patients with no bone involvement (figure 4). BSP expression was significantly increased in infiltrating ductal carcinoma compared to infiltrating lobular carcinoma (p = 0.0023). No correlation was found between immunoreactivity to BSP antibodies and ER status, PR status or age. Our data suggest that BSP could help to identify which women will develop bone metastases and provide new bases for the understanding of the molecular mechanism(s) responsible for breast cancer cells osteotropism.

We have next examined the prognostic value of BSP on a large retrospective series of 454 breast cancer patients followed up for at least 20 years (Bellahcène et al., 1996c). We found that expression of BSP in primary breast cancers was significantly associated with poor prognosis (figure 5). There was a significant association between BSP expression in the primary tumor and axillary lymph node involvement. Patients with positive lymph nodes but BSP-negative tumors had a better survival than lymph node negative patients but with BSP-positive breast cancers (table II). This observation is interesting since it indicates that BSP detection could help to identify, within the group of breast cancer patients with negative axillary lymph nodes, the ones at high risk of disease progression. Because of early detection of breast cancer, the axillary lymph node status has less prognostic significance. Also, it is a major challenge to identify reliable predictors of the metastatic potential of lymph node negative breast cancer. If BSP production by the primary tumors provides a means of identifying those at risk of progression, it will allow the selection of lymph node negative patients most likely to benefit from specific adjuvant treatments. BSP is a secreted protein that can be detected in the serum (Chenu and Delmas, 1992). If the expression of BSP by breast cancer cells results in a significant increase of serum BSP levels, then RIA or ELISA assays in the serum of breast cancer patients could be a quantitative assay used for clinical evaluation. We found a significant correlation between BSP expression and lung metastases as the first site of metastatic dissemination. In fact, patients whose tumors were BSP-positive were less likely to develop lung metastases. The observation that BSP-positive tumors metastasize preferentially to bone rather than to lung suggests that the expression of this bone matrix protein by breast cancer cells plays a role in their selective affinity for the skeleton. Ongoing prospective studies should confirm the value of BSP detection in primary breast cancers to permit evaluation of overall prognosis and risk for specific metastatic sites.

Hypothetic role(s) of BSP in mediating interactions between breast cancer cells and bone

After they have left the primary tumor, invaded the surrounding tissues and intravasated into the bloodstream, metastatic breast cancer cells are then "seeded" to the sinusoids in the medullary cavity, or the Volkmann and Haversian canals in the cortex of the bone (Boyce, 1991). There, tumor cells are believed to adhere to the endothelium in the marrow (Haq et al., 1992). Extravasation out of the vascular system is facilitated by the unique structure of the arteries in the medullar cavity. These vessels branch into single layered sinusoid and cortical capillaries which lack a basement membrane and have a 60 Å gaps that permit the tumor cells to exit into the marrow cavity. The exact site(s) of attachment within bone may involve specific receptors on bone marrow endothelial cells. Once the bone tissue reached, cancer cells must establish privileged interactions with the host sites in order to implant and develop into a secondary flourishing colony.

The exact molecular mechanisms involved in the selective interaction of breast cancer cells with the bone matrix are not yet identified. The demonstration of a positive association between expression of BSP in malignant mammary tumors and the development of bone metastases suggests that this phosphoprotein could play a biological role in the complex process that leads to the selective implantation of breast cancer cells to the skeleton. It has been shown that BSP-coated plastic surfaces promote the attachment of both osteoblasts (Oldberg et al., 1988) and osteoclasts (Miyauchi et al., 1991). The primary structure of BSP contains an RGD (Arg-Gly-Asp) domain that confers to BSP its cell binding activity. The RGD sequence is an integrin-recognition motif and it is now well established that osteoclasts bind to BSP via an avb3 integrin-type receptor (Ross et al., 1993). It is tempting to suggest that this interaction may represent a mechanism by which circulating breast cancer cells bind to bone. Our speculative model postulates that breast cancer cells coated with BSP could establish privileged interaction with mineralized bone matrix, an early step determinant for the establishment of the metastatic colonies. Although this model needs to be tested, it is in agreement with recent studies that have demonstrated that breast cancer cell lines do attach to BSP via integrin-type receptors (van der Pluijm et al., 1993; 1995). Our work opens new alleys of investigations that could contribute to the understanding of the mechanisms of bone metastasis formation and potentially could help define new strategies to prevent, predict and treat bone metastases.

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