The small G-protein RalA stimulates metastasis of transformed cells.

RAS oncogenes play a critical role in oncogenic transformation and metastases formation. Here we show that Ha-ras greatly stimulates spontaneous metastatic activity of transformed cells through the Ras/RalGDS/RalA intracellular signaling pathway. Introduction of RalA alone leads to a drastic increase of metastatic activity of transformed cells. We demonstrate that metastatic ability of cells could be dramatically enhanced by RalA stimulation or, conversely, hampered by RalA suppression. Furthermore, we found that during in vivo selection cells acquire high metastatic properties as a result of endogenous RalA activation. The ability of RalA to induce metastasis was demonstrated in spontaneously transformed as well as in virus transformed fibroblasts.

CRABP1 provides high malignancy of transformed mesenchymal cells and contributes to the pathogenesis of mesenchymal and neuroendocrine tumors.

CRABP1 (cellular retinoic acid binding protein 1) belongs to the family of fatty acid binding proteins. Retinoic acid binding is the only known functional activity of this protein. The role of CRABP1 in human carcinogenesis remains poorly understood. Here, for the first time we demonstrated pro-metastatic and pro-tumorigenic activity of CRABP1 in mesenchymal tumors. Further functional analysis revealed that the pro-tumorigenic effect of CRABP1 does not depend on retinoic acid binding activity. These results suggest that CRABP1 could have an alternative intracellular functional activity that contributes to the high malignancy of transformed mesenchymal cells. Microarray analysis detected CRABP1-mediated alterations in the expression of about 100 genes, including those encoding key regulatory proteins. CRABP1 is ubiquitously expressed in monophasic synovial sarcomas, while in biphasic synovial sarcomas it is expressed uniquely by the spindle cells of the aggressive mesenchymal component. High level of CRABP1 expression is associated with lymph node metastasis and poor differentiation/high grade of pancreatic neuroendocrine tumors (pNETs). Presented data suggest CRABP1 as a promising biomarker of pNETs' clinical behavior. Our results give the first evidence of pro-tumorigenic and pro-metastatic activity of CRABP1 in mesenchymal and neuroendocrine tumors.

Alternative production of Bcl-2 and Bax by tumor cells determines the rates of in vivo tumor progression: suggested mechanisms.

The hypothesis tested in the study suggests that mechanisms of the earlier described delayed or accelerated tumor progression may be regulated by the antiapoptotic and proapoptotic cellular programs activated in stress reactions of transformed cells to the host normal cellular environment. Therefore, spontaneously transformed hamster cell line STHE, its bcl-2-transduced line STHE-Bcl-2, and 64 of their descendant tumor cell variants naturally selected in two in vivo regimes (local tumor growth versus dissemination) were examined. The role of Bcl-2 and the possible activation of endogenous death-signaling Bax, Ras, and HSP90/HSP70 stress proteins in STHE (Bcl-2+/-) tumor cell variants were studied in dynamics of in vivo tumor progression. The data demonstrate: (1) Immediate in vivo activation of Bax and of HSP90/HSP70 stress proteins in disseminated STHE cells on the background of accelerated tumor progression; (2) No immediate activation of Bax and the gradual downregulation of Bcl-2 in STHE-Bcl-2 cells on the background of delayed tumor progression; (3) Alternative and mutually suppressive character of Bcl-2 and Bax expression in both regimes of tumor progression; (4) In the later stages of tumor progression, the regular transit of the initial Bcl-2 antiapoptotic, Bax-suppressing program, and the delayed tumor progression towards Bcl-2 loss, activation of Bax, and acceleration of tumor progression. Thus, the delay of tumor progression is apparently determined by the ability of Bcl-2-expressing tumor cells to extinguish the cell-damaging environmental stress signals and Bax activation, while its acceleration correlates with Bcl-2 loss, activation of proapoptotic Bax, and tumor cells damage.