Correspondence
Molecular Basis of Metastasis
N Engl J Med 2009; 360:1678-1680April 16, 2009
- Article
To the Editor:
In their review article, Chiang and Massagué (Dec. 25 issue)1 give limited attention to the intravascular phase of the metastatic process. With the exception of cells in hematopoietic cancers, tumor cells do not typically circulate as independent entities (as depicted in Fig. 2 and 3 of the article). Rather, they are usually found in clumps, surrounded by a “cloak” of platelets and leukocytes.2,3 This fact is of more than just academic interest. First, this is the phase in which the vast majority of potentially metastatic malignant cells perish, with the few surviving cells ultimately leading to the death of the patient. Second, such tumor emboli can persist in the vasculature for some time,2,3 when intravasation is assisted by normal blood elements.4 Third, much is known about adhesion molecules, coagulation pathways, and other molecular contributors to this phase of metastasis.4,5 Last but not least, this is the step of metastasis in which therapeutic intervention has a chance of being successful.5 Indeed, there is good evidence that the well-known antimetastatic effects of heparin involve interdiction of some of these intravascular interactions.3-5
5 ReferencesAjit Varki, M.D.
Nissi M. Varki, M.D.
University of California, San Diego, La Jolla, CA 92093Lubor Borsig, Ph.D.
University of Zurich, CH-8057 Zurich, Switzerland1
Chiang AC ,Massague J . Molecular basis of metastasis. N Engl J Med 2008;359:2814-2823
Full Text | Web of Science | Medline2
Al-Mehdi AB ,Tozawa K ,Fisher AB ,Shientag L ,Lee A ,Muschel RJ . Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 2000;6:100-102
CrossRef | Web of Science | Medline3
Borsig L ,Wong R ,Hynes RO ,Varki NM ,Varki A . Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A 2002;99:2193-2198
CrossRef | Web of Science | Medline4
Laubli H ,Stevenson JL ,Varki A ,Varki NM ,Borsig L . L-selectin facilitation of metastasis involves temporal induction of Fut7-dependent ligands at sites of tumor cell arrest. Cancer Res 2006;66:1536-1542
CrossRef | Web of Science | Medline5
Varki NM ,Varki A . Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Semin Thromb Hemost 2002;28:53-66
CrossRef | Web of Science | Medline
To the Editor:
We suggest that the “cancer cell–centric” perspective of metastasis overlooks the local microenvironment at distant sites. It appears that a premetastatic niche develops from recruited hematopoietic cells1 during tumor onset and progression. This niche is probably due to necrosis and inflammation.2,3 The importance of site-specific inflammation in metastasis has been shown in a study4 in which pulmonary inflammation due to extended provocation of an allergic respiratory reaction enhanced metastasis to the lung in a mouse tumor model. More importantly, among patients with breast cancer, the incidence of lung metastases was approximately twice as high among patients with asthma as among patients without asthma.
4 ReferencesJames J. Lee, Ph.D.
Mayo Clinic Arizona, Scottsdale, AZ 85259
jjlee@mayo.edu Michael T. Lotze, M.D.
University of Pittsburgh Cancer Institute, Pittsburgh, PA 152131
Kaplan RN ,Rafii S ,Lyden D . Preparing the “soil”: the premetastatic niche. Cancer Res 2006;66:11089-11093
CrossRef | Web of Science | Medline2
Vakkila J ,Lotze MT . Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004;4:641-648
CrossRef | Web of Science | Medline3
DeNardo DG ,Johansson M ,Coussens LM . Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 2008;27:11-18
CrossRef | Web of Science | Medline4
Taranova AG ,Maldonado D III ,Vachon CM , et al. Allergic pulmonary inflammation promotes the recruitment of circulating tumor cells to the lung. Cancer Res 2008;68:8582-8589
CrossRef | Web of Science | Medline
To the Editor:
In their review article, Chiang and Massagué discuss the environment of the primary tumor, and they stress the importance of reduced cell–cell adhesion through down-regulation of E-cadherin expression in metastasis. We would like to add the concept of cell–cell dysadhesion through expression of dysadherin, a cancer-associated cell-membrane glycoprotein. Dysadherin expression is associated with in vitro and in vivo cancer metastasis.1 In many tumors (e.g., thyroid, tongue, and other head and neck carcinomas) it acts through post-transcriptional down-regulation of E-cadherin. In others (e.g., melanoma and breast, pancreatic, colorectal, gastric, and non–small-cell lung carcinomas), dysadherin's prometastatic effects appear to be independent of E-cadherin and possibly related to up-regulation of chemokines. Thus, dysadherin concomitantly modulates the neoplastic cells and their stromal environment, facilitating metastasis. Another issue is the establishment of the neoplastic cells in their metastatic site and their growth to a tumor mass. For this process, it has been shown that the reestablishment of neoplastic cell–cell adhesion is necessary through restoration of the expression of E-cadherin and the loss of expression of dysadherin.2
2 ReferencesAnna Batistatou, M.D., Ph.D.
Alexander Charalabopoulos, M.D.
Konstantinos Charalabopoulos, M.D., Ph.D.
University of Ioannina, 41010 Ioannina, Greece
abatista@cc.uoi. gr 1
Nam J-S ,Hirohashi S ,Wakefield LM . Dysadherin: a new player in cancer progression. Cancer Lett 2007;255:161-169
CrossRef | Web of Science | Medline2
Batistatou A ,Charalabopoulos A ,Scopa CD , et al. Expression patterns of dysadherin and E-cadherin in lymph node metastases of colorectal carcinoma. Virchows Arch 2006;448:763-767
CrossRef | Web of Science | Medline
Author/Editor Response
Several letters to the editor highlight aspects of metastasis that certainly deserve attention and involve active areas of research, but these topics could not be covered in our review article. Additional aspects of metastasis warrant commentary. Varki et al. point to intravascular “premetastatic” events — in particular, the role of platelets and leukocytes in forming and protecting tumor emboli, mediating cancer-cell adhesion, and producing metabolites and factors that spur growth and invasion. The ongoing dialogue of tumor cells with the immediate microenvironment occurs during transit and at the premetastatic niche in a distant site.
The intriguing link between inflammation and cancer progression may occur through site-specific inflammatory infiltrates, which allow tumor initiation and colonization in the primary site.1 As Lee and Lotze mention, these infiltrates also occur in the premetastatic niche in the lung. We refer to how selective pressures of the local tumor environment can modify tumor cells, and recent evidence from animal models provides further support for the idea that paracrine interactions may also attract nontumor (e.g., bone marrow–derived) and tumor cells to establish a premetastatic niche.2,3 The active dysadhesion of local tissues to allow tumor-cell invasion (e.g., via E-cadherin, dysadherin, or both) is also probably triggered by paracrine signaling, as Batistatou et al. point out. Finally, the complex roles played by the host-site microenvironment and by the immune system in metastatic dormancy are not yet fully understood, although recent intriguing results point to tumor-specific T-cell suppression of multistage carcinogenesis through cytokine signaling.4
4 ReferencesAnne Chiang, M.D., Ph.D.
Joan Massagué, Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
massaguj@mskcc.org 1
Bromberg J ,Wang TC . Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 2009;15:79-80
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Hiratsuka S ,Watanabe A ,Sakurai Y , et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 2008;10:1349-1355
CrossRef | Web of Science | Medline3
Erler JT ,Bennewith KL ,Cox TR , et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 2009;15:35-44
CrossRef | Web of Science | Medline4
Muller-Hermelink N ,Braumuller H ,Pichler B , et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 2008;13:507-518
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Martin Schlesinger, Patrick Schmitz, Reiner Zeisig, Annamaria Naggi, Giangiacomo Torri, Benito Casu, Gerd Bendas. (2011) The inhibition of the integrin VLA-4 in MV3 melanoma cell binding by non-anticoagulant heparin derivatives. Thrombosis Research
CrossRef2
Denis Wirtz, Konstantinos Konstantopoulos, Peter C. Searson. (2011) The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nature Reviews Cancer 11:7, 512-522
CrossRef
