Myriam Labelle

The Initial Hours of Metastasis: The Importance of Cooperative Host–Tumor Cell Interactions during Hematogenous Dissemination

UNLABELLED Tumor cells transit from the primary tumor via the blood circulation to form metastases in distant organs. During this process, tumor cells encounter a number of environmental challenges and stimuli that profoundly impact their metastatic potential. Here, we review the cooperative and dynamic host-tumor cell interactions that support and promote the hematogenous dissemination of cancer cells to sites of distant metastasis. In particular, we discuss what is known about the cross-talk occurring among tumor cells, platelets, leukocytes, and endothelial cells and how these cell-cell interactions are organized both temporally and spatially at sites of extravasation and in the early metastatic niche. SIGNIFICANCE Metastasis is a function not only of tumor cells but also involves cooperative interactions of those cells with normal cells of the body, in particular platelets and leukocytes. These other cell types alter the behavior of the tumor cells themselves and of endothelial cells lining the vasculature and assist in tumor cell arrest and extravasation at sites of metastasis and subsequently in the establishment of tumor cells in the early metastatic niche. A better understanding of the important role that these contact and paracrine interactions play during metastasis will offer new opportunities for therapeutic intervention.

Platelets guide the formation of early metastatic niches

Significance Specialized microenvironments (or “niches”) are essential for metastasis, but how cancer cells and host cells contribute to their establishment remains poorly understood. Our study reveals that platelets and granulocytes are sequentially recruited to disseminated tumor cells to form “early metastatic niches” that promote metastatic progression. Importantly, the recruitment of granulocytes is not primarily due to tumor cell-derived signals but rather relies on platelet-derived CXCL5/7 chemokines. Prevention of granulocyte recruitment via inhibition of the CXCL5/7 receptor CXCR2, or depletion of either platelets or granulocytes inhibits metastasis, thereby uncovering a key role for platelet-to-granulocyte signaling in the establishment of metastases. Specific inhibition of platelet-to-granulocyte interactions may thus represent a valuable antimetastatic therapy in addition to cancer cell-centered treatments. During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments (“niches”) that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to tumor cells to form “early metastatic niches.” Granulocyte recruitment relies on the secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells. Blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, platelets recruit granulocytes and guide the formation of early metastatic niches, which are crucial for metastasis.

Interplay between neural-cadherin and vascular endothelial-cadherin in breast cancer progression

IntroductionDeregulation of cadherin expression, in particular the loss of epithelial (E)-cadherin and gain of neural (N)-cadherin, has been implicated in carcinoma progression. We previously showed that endothelial cell-specific vascular endothelial (VE)-cadherin can be expressed aberrantly on tumor cells both in human breast cancer and in experimental mouse mammary carcinoma. Functional analyses revealed that VE-cadherin promotes tumor cell proliferation and invasion by stimulating transforming growth factor (TGF)-β signaling. Here, we investigate the functional interplay between N-cadherin and VE-cadherin in breast cancer.MethodsThe expression of N-cadherin and VE-cadherin was evaluated by immunohistochemistry in a tissue microarray with 84 invasive human breast carcinomas. VE-cadherin and N-cadherin expression in mouse mammary carcinoma cells was manipulated by RNA interference or overexpression, and cells were then analyzed by immunofluorescence, reverse transcriptase-polymerase chain reaction, and western blot. Experimental tumors were generated by transplantation of the modified mouse mammary carcinoma cells into immunocompetent mice. Tumor growth was monitored, and tumor tissue was subjected to histological analysis.ResultsVE-cadherin and N-cadherin were largely co-expressed in invasive human breast cancers. Silencing of N-cadherin in mouse mammary carcinoma cells led to decreased VE-cadherin expression and induced changes indicative of mesenchymal-epithelial transition, as indicated by re-induction of E-cadherin, localization of β-catenin at the cell membrane, decreased expression of vimentin and SIP1, and gain of epithelial morphology. Suppression of N-cadherin expression also inhibited tumor growth in vivo, even when VE-cadherin expression was forced.ConclusionsOur results highlight the critical role of N-cadherin in breast cancer progression and show that N-cadherin is involved in maintaining the malignant tumor cell phenotype. The presence of N-cadherin prevents the re-expression of E-cadherin and localization of β-catenin at the plasma membrane of mesenchymal mammary carcinoma cells. N-cadherin is also required to maintain the expression of VE-cadherin in malignant tumor cells but not vice versa. Thus, N-cadherin acts in concert with VE-cadherin to promote tumor growth.

Abstract IA25: Signaling roles of platelets during metastatic seeding

Abstracts: AACR Special Conference on Tumor Metastasis; November 30-December 3, 2015; Austin, TX During metastasis, host cells are recruited to disseminated tumor cells to form dynamic, specialized microenvironments (niches) that promote metastatic progression. Platelets interact with tumor cells during their transit through the circulation and are key components of the early metastatic niches, which are formed when tumor cells initially arrest in distant organs. Interestingly, high platelet counts are frequently associated with poor outcome and disease progression in patients with solid tumors. Coincident with these clinical observations, platelets have been shown to promote metastasis via multiple mechanisms, including their ability to form physical shields around tumor cells, which prevent attacks from natural killer (NK) cells and facilitate tumor cell adhesion to the endothelium. However, in addition to these adhesive properties, platelets contain several signaling factors, which are released upon platelet activation, raising the possibility that platelet-derived signals modulate the metastatic potential of tumor cells and the function of host cells present in metastatic niches. We tested this hypothesis and found that direct contact between platelets and tumor cells triggers EMT (epithelial-mesenchymal transition) via activation of the TGFβ1 and NF-κB signaling pathways in tumor cells. We further showed that these two signaling pathways synergize to enhance the invasive potential of tumor cells and increase their ability to extravasate and seed metastases in vivo. Thus, cancer cells rely on platelet-derived signals provided in the early metastatic niche for efficient metastasis. In addition, we found that platelets influence metastasis by signaling not only to tumor cells but also to host cells present in the same metastatic niches. Importantly, platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to early metastatic niches. Granulocyte recruitment relies on CXCL5 and CXCL7 chemokines, which are released by platelets upon contact with tumor cells. Furthermore, blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, in addition to promoting metastasis via direct platelet-to-tumor cell signaling, platelets are required for the recruitment of prometastatic granulocytes to early metastatic niches. Overall, our work establishes platelets as key signaling platforms during metastatic seeding. On this basis, we propose that specific inhibition of platelet-to-tumor cell or platelet-to-granulocyte signaling may represent valuable antimetastatic interventions in combination with cancer cell-centered treatments. References: Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011 Nov 15;20(5):576-90. Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3053-61. Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012 Dec;2(12):1091-9. Citation Format: Myriam Labelle. Signaling roles of platelets during metastatic seeding. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA25.