PII S0361-9230(00)00379-8 Molecular mechanisms of tumor dissemination in primary and metastatic brain cancers Georg F. Weber 1,2 * and Samy Ashkar 3 1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA; 2 Department of Medicine, Harvard Medical School, Boston, MA, USA; and 3 Laboratory for Skeletal Disorders and Rehabilitation, Children’s Hospital, Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, USA [Received 29 July 2000; Accepted 1 August 2000] ABSTRACT: Cancer is characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. Tumor dissemination distinguishes malignant from benign neoplasms and is mediated by homing receptors, their ligands, and proteinases. The homing receptor CD44 is fre- quently expressed on primary brain tumors and brain metasta- ses. Its engagement by osteopontin physiologically induces macrophage chemotaxis, a mechanism that may be utilized by metastatic brain tumors in the process of dissemination. In host defense, osteopontin and its receptors, CD44 and integrin  V  3 , play key roles in mediating delayed type hypersensitivity re- sponses by activating macrophages to induce Th1 cytokines while inhibiting Th2 cytokines. Other metastasis associated gene products similarly contribute to host defenses. Hence, cancer spread is regulated by a set of developmentally non- essential genes which physiologically mediate stress re- sponses, inflammation, wound healing, and neovascularization. Function of the relevant gene products is extensively modified post-transcriptionally and their dysregulation in cancer occurs on the levels of expression and splicing. Consistent patterns of organ preference by malignancies of particular tissue origin suggest a necessary connection between loss of growth con- trol and senescence genes and expression of genes mediating the dissemination of tumor cells. © 2000 Elsevier Science Inc. KEY WORDS: Invasion, Homing receptors, Cytokines, Protein- ases, Stress response. MOLECULAR CHARACTERISTICS OF CANCER The most prominent feature of malignancy is dysregulated cell cycle progression. Division of cancer cells leads to formation of more cancer cells indicating that the characteristics of transforma- tion originate in genetic changes. The underlying defects causing uncontrolled proliferation are gain of function mutations in onco- genes or loss of function mutations in tumor suppressor genes. However, most somatic cells, with few exceptions such as stem cells, die after a finite number of cell divisions, a phenomenon described as senescence. Replicative senescence begins after fer- tilization and is genetically dominantly controlled. For cancer to occur, there must be a loss of function in senescence genes or a gain of function in telomerase to give rise to a largely unlimited number of cell divisions. Finally, cancer is distinguished from benign tumors by its faculty to generate metastases. In contrast to earlier models, metastasis formation is a process of active cell migration and invasion rather than the passive dyslocation of cells in the blood or lymph flow. Whether a neoplasm metastasizes and to which target organs is determined by motility associated mol- ecules expressed by the tumor cells. INVASIVENESS OF BRAIN TUMORS The brain is unique as a target organ for metastatic growth because it is surrounded by the blood— brain barrier and it lacks lymphatic drainage. Nevertheless, certain malignancies display a preference for dissemination to the central nervous system (CNS). Brain metastases from colon and breast cancers are often single, whereas melanoma and lung cancer have a greater tendency to produce multiple colonies. At autopsy, up to 80% of melanoma patients have CNS lesions [20]. Invasion of brain cancer cells typically proceeds along anatomic structures that are rich in ex- tracellular matrix proteins, including basement membranes of blood vessels and the glial limitans externa [4] and has been attributed to specific motility-associated receptors, their ligands and proteinases [6] (Table 1). Specifically, the homing receptor CD44 is frequently expressed on primary brain tumors and brain metastases [10,12,15]. Its ligand osteopontin has also been de- scribed to be secreted by malignant gliomas [5,16,22]. THE PHYSIOLOGIC ROLES OF METASTASIS GENES To understand the process of metastasis formation we have studied the physiologic importance of the relevant gene products. We have investigated the cytokine osteopontin and its receptor CD44 [25–27]. The engagement of CD44 by osteopontin induces macrophage chemotaxis, a process that may be utilized by meta- static brain tumors in the process of dissemination [26]. Gene- targeted mice deficient in osteopontin or CD44 are fertile and developmentally normal, a trait that is shared by other knockouts for genes that are believed to be important in metastatic spread. Several observations implied that osteopontin may act as a stress * Address for correspondence: Dr. Georg F. Weber, New England Medical Center, 750 Washington Street, NEMC #824, Boston, MA 02111, USA. Fax: +1-(617)-636-1766; E-mail: GWeber@lifespan.org Brain Research Bulletin, Vol. 53, No. 4, pp. 421– 424, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/00/$–see front matter 421