Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes?

Abstract

Evidence is reviewed which suggests a linkage may exist between certain forms of de novo or acquired drug resistance and metastasis. This includes the finding that expression of certain dominantly acting mutant oncogenes or tumor suppressor genes, i.e., genes which normally act to "drive" tumor progression and metastasis, can also affect the expression of drug resistance. Moreover, this can be accompanied by altered expression of certain cellular genes thought to be involved in expression of drug resistance. A direct linkage between acquired drug resistance and metastasis would suggest that tumor sublines selected for drug resistance should manifest more aggressive malignant properties than their drug-sensitive counterparts. While this does not appear to be true for drug resistant sublines selected in vitro, indeed such cell lines frequently manifest diminished in vivo tumorigenic and/or metastatic competence, there is some evidence to support such a correlation exists for tumor cell lines that are selected in vivo for drug resistance. Attention is also drawn to the fact that new linkages between metastasis and drug resistance may be uncovered by analyzing the ability of tumor subpopulations to acquire drug resistance after one or several previous exposures to chemotherapeutic drugs, as opposed to examining intrinsic drug resistance only. Furthermore, ability to detect induced or acquired drug resistance in vitro may be strongly influenced by the types of assay used to detect and monitor drug resistance. In particular, three-dimensional cell culture systems may reveal acquired or induced "multicellular" drug resistance in situations where conventional two-dimensional culture systems do not. Use of three-dimensional culture systems may therefore reveal as yet undiscovered associations between the phenotypes of metastasis and drug resistance.

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

“…Thus, it is not surprising that NCI-N87-S120 xenografts grew significantly slower in the mice than NCI-N87, which is consistent with the notion that drug-resistant tumor sublines selected in vitro frequently manifest less aggressive properties than their drugsensitive parental cell lines (49). Nevertheless, in vivo studies show that the NCI-N87-S120 xenograft retained ABCG2 expression and was resistant to IMMU-132, yet its growth could be significantly subdued by IMMU-132 in combination with YHO-13351.…”

Tissue transgluaminase 2 expression in meningiomas

“…High expression levels of TG2 have also been associated with resistance to chemotherapy in multiple tumor cell lines [18,19]. Changes in tumor phenotype associated with drug-resistance have been associated with metastatic potential [20,21]. For example, interaction between integrin α 5 and fibronectin is necessary for metastasis of B16 murine melanoma cells [22].…”

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

“…These drug-resistant cell lines (particularly the CPT-resistant variant) were much more efficient at forming spontaneous lung metastases after s.c. injection of cells in comparison to the drug-sensitive parental line. 28,29 Using the method of Teicher et al, 27 Mitsumoto et al 30 established 2 CPTresistant mouse epithelial tumour cell lines with enhanced metastatic capabilities associated with higher levels of cell adhesion to ECM components, such as fibronectin, laminin, collagen type IV and Matrigel; enhanced MMP-2 activity; and higher levels of cell motility. Van Putten et al 31 showed that treatment of animals bearing a transplantable osteosarcoma with cyclophosphamide or CCNU resulted in a significant increase in lung metastases compared to controls.…”