Overexpression of Carcinoma and Embryonic Cytotrophoblast Cell-Specific Mig-7 Induces Invasion and Vessel-Like Structure Formation

Abstract

Molecular requirements for carcinoma cell interactions with the microenvironment are critical for disease progression but are poorly understood. Integrin ␣v␤5, which senses the extracellular matrix, is important for carcinoma cell dissemination in vivo. ␣v␤5 signaling induces Mig-7, a novel human gene product that is apparently carcinoma-specific. We hypothesized that Mig-7 expression facilitates tumor cell dissemination by increasing invasion and vasculogenic mimicry. Results show that embryonic cytotrophoblasts up-regulated Mig-7 expression before they acquired an invasive phenotype capable of pseudovasculogenesis. Mig-7 protein primarily co-localized with vasculogenic mimicry markers factor VIII-associated antigen, vascular endothelial-cadherin, and laminin 5 ␥2 chain domain III fragment in lymph node metastases. Overexpression of Mig-7 increased ␥2 chain domain III fragments known to contain epidermal growth factor (EGF)-like repeats that can activate EGF receptor. Interestingly, EGF also induced Mig-7 expression. Carcinoma cell adhesion to laminins was significantly reduced by Mig-7 expression. Remarkably, in two-dimensional and three-dimensional Matrigel cultures, Mig-7 expression caused invasion and vessel-like structures. Melanoma cells, which were previously characterized to invade aggressively and to undergo vasculogenic mimicry, expressed Mig-7. Taken together, these data suggest that Mig-7 expression allows cells to sense their environment, to invade, and to form vessel-like structures through a novel relationship with laminin 5 ␥2 chain domain III fragments.

Mig-7 expression and vasculogenic mimicry in malignant ovarian tumors

“…Taken together, these observations suggest that high expressions of MIG-7 in tumor tissues concurrent with high expression of VE-cadherin may have a synergistic effect that promotes VM formation. Similar results were reported by Petty et al [17] when these investigators analyzed MIG-7 expression in breast cancer. They have demonstrated the specificity of MIG-7 expression to breast cancer tissue as MIG-7 was not detected in normal breast tissues nor it was found in blood from normal subjects.…”

“…To date, MIG-7 protein was found to be localized on normal embryonic cytotrophoblast cells and on cancer cells as well as within the lumen of vessel-like structures. Immunohistochemistry demonstrated that MIG-7 protein co-localizes with endothelial marker factor VIII, VE-cadherin and laminin 5 γ2 domain fragment III [17].…”

“…MIG-7 protein induces invasion and vessel-like structure formation by cancer cells in three dimensional (3D) cultures in vitro and the knockdown of MIG-7 gene in cancer cells line causes their reduced invasion in 3D cultures. The gene activation promotes lung cancer metastases formation by activating the cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling cascade [17]. Immunohistochemical (IHC) studies performed with MIG-7 antibodies revealed expression of this marker in circulating tumor cells, proposing its potential as an early marker for metastatic carcinomas [18,19].…”

Mig-7 Linked to Vasculogenic Mimicry

“…In this issue of The American Journal of Pathology, Petty et al report that expression of a relatively understudied protein called migration-inducing protein 7 (MIG7 or Mig-7) facilitates tumor cell dissemination by increasing invasion and promoting the process of vasculogenic mimicry. 1 Vessels that form during tumorigenesis are usually lined by an endothelium, but abnormal vessel development in which cancer cells directly line vessels or blood channels within tumors have been described and termed vasculogenic mimicry. [2][3][4][5] One of the earliest descriptions of these tumor-lined vasculogenic channels was by Willis, who stated in 1948 that "in rapidly growing tumors, [vessels] consist of little more than irregular channels lined by endothelium only or by naked tumor cells.…”

“…1 However, the complete pathophysiological significance of these structures in the tumorigenic process remains to be fully elucidated in animal models. 14 It is predicted that these structures may serve as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process; however, this possibility remains controversial.…”