Gene Overexpression And Downregulation

Invasiveness and metastatic ability of the neoplastic cells appear as a result of accumulation of newly acquired genetic alterations beyond those that initiate oncogenesis.7 Some of these alterations may include more than a few genes.8 Mutations occur at a higher rate in cancer cells because their genetic material (chromosomes or DNA) is intrinsically unstable.17 This genetic instability seems to be a "property" of cancer cells. Abnormalities (i.e., loss or gain of chromosomal material) are rather frequent in solid tumors and have been associated with high-grade malignan-cies.17,18 During the stepwise progression of cancer, oncogenes are either activated or inactivated, mutation or deletions occur in normal suppressor genes, and there is gene amplification of promotion associated genes and growth factors. Thus, the association between oncogene alterations and prognosis has been extensively investigated, and the demonstration of oncogene amplification is a valuable prognostic marker in certain tumors. Certain genes, such as p53,

Metastasis

Distant tumor growth and homing

Local tumor growth and invasion

Bloodstream dissemination

Local tumor growth and invasion

Angiogenesis

Angiogenesis

Metastasis

Distant tumor growth and homing

Bloodstream dissemination

FIGURE 4.3. After an organ has been invaded, distant metastasis is the result of growth in a distant tissue facilitated by tissue receptors (homing), on-site angiogenesis, and cell survival after immune response of the host.

motic connections to the external carotid circulation.20 The right carotid originates together with the subclavia from the brachiocephalic trunk, whereas the left carotid system originates directly from the aorta.21 Within the orbit, the ophthalmic artery gives off posterior ciliary vessels and multiple muscular branches, which give rise to the anterior ciliary vessels.22 These arteries lead into the marginal and peripheral arterial arcades of the eyelid, with anastomoses from the maxillary branch of the external carotid artery. Blood vessels and connective tissue form an integrated system. The microvascular system is predominantly confined to the adipose tissue compartments. The interrelationships of the vascular system and the connective tissue system are likely to be important factors in controlling and regulating orbital blood flow.

Early studies suggested that orbital metastases were more frequent on the left side. This suggestion was supported by the direct origin of the left common carotid artery from the aorta. However, recent reviews of reported series and case reports revealed that unilateral involvement was very similar in both sides, and both sides are simultaneously affected in 7% of cases.23

The presence of orbital lymphatics in a primate model was demonstrated by using light and electron microscopic enzyme histochemistry.24 Lymphatic vessels were identified in the lacrimal gland and in the dura mater of the optic nerve. In addition, structures demonstrating positive staining markers at the orbital apex were highly suggestive of lymphatics but did not meet the morphologic criteria established.25 Lymphatic vessels were not identified in the extraocular muscles or orbital fat in other studies.26 Traditionally, lymph node dissemination from ocular and orbital tumors requires prior invasion of the conjunctiva and eyelid, where lymphatic channels are constitutively present.

Orbital Tissue Homing

Based on the presence of different tissue components within the orbit (i.e., bone, striated muscle, fat and connective tissue, lacrimal gland), some tumors appear to disclose specific homing tissue patterns. "Homing" refers to cell trafficking to specific tissues and organs that appears to be regulated by tissue- or cell-specific adhesion molecules and receptors critical to the extravasations process. This may reflect some degree of organ tropism or the production of tumor cells and host cells of some sort of products that specifically bind to or favor the survival and growth of the mestastatic cells. In addition, circulating tumor cells may adhere specifically to the endothelial cells only in the target organ. The expression of particular genes has been recently shown to be associated with the development of metastasis of certain tumors in a par ticular organ. In addition, preferential growth may be induced by the local microenvironment.

Adhesion of circulating cells to endothelial cells is mediated by a variety of cell adhesion molecules. The first steps in the cell adhesion cascade (rolling and tethering) are regulated by selectins (P, E, and L se-lectin). The following steps of stable adhesion and transmural migration predominantly involve integrins (LFA-1).27

Although homing patterns are relatively well known for normal and neoplastic lymphocytes, the mechanisms for tissue- or organ-specific homing in solid tumors are not fully understood. CD44 is a family of transmembrane glycoproteins encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing.28 Some variant isoforms, especially those containing sequences encoded by v6 to v10, might be related to capillary-lymphatic space invasion and metastasis and are overexpressed in both human and animal neo-plasms.29 In a rat pancreatic adenocarcinoma model, one of the variant CD44 isoforms was proven to be determinant in the metastatic process. For some human neoplasms (e.g., carcinomas of the digestive tract, thyroid carcinomas, poorly differentiated endometri-oid adenocarcinomas) correlations have been made between the particular pattern of CD44 variants (CD44v6) produced by neoplastic cells and clinico-pathological parameters of tumors, such as grade, stage, presence of metastases, and survival. CD44 in normal cells acts mainly as a receptor for hyaluronan and has an affinity for other extracellular matrix li-gands such as fibronectin, serglycin, and osteopontin. In orbital diseases, CD44 receptors have been observed in patients with Graves ophthalmopathy, characterized by increased amounts of hyaluronic acid in the extracellular matrix and infiltration by lymphocytes.30

Chemoattraction is another mechanism to direct the migration of tumor cells from their primary site via the circulation to preferential targets of metas-tases.31 The findings indicate that certain chemokine receptors are found on breast cancer cells, and their ligands are highly expressed at sites associated with breast cancer metastases.32

As mentioned, tumor cells express adhesion molecules in the integrin family, and these receptors play a pivotal role in the development of a meta-static colony. Several integrin subunits (a2, a4, f}3) were found to have increased expression in orbital metastatic lesions from prostate carcinoma, malignant melanoma, and lobular breast carcinoma in comparison to normal prostate tissue and normal melanocytes.33 The increased expression of these in-tegrins may be responsible for the tendency of these tumors to metastasize to the orbit, as well as for the tendency of prostate tumors to metastasize preferentially to orbital bones.

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