Osteotropism Of Metastatic Dissemination

Metastatic spread of cancer is a nonrandom process. The perceived organ specificity of metastasis can be attributed to a variety of factors intrinsic to the cancer cell as well as to the target organs (see Sherbet, 1982 for review). Metastatic spread to the bone is a common occurrence in certain forms of cancer. It has been argued often that bone metastases can activate the processes of bone metabolism. For that reason osteocalcin has been regarded as a potential surrogate method for detecting metastatic spread as well as for the purpose of monitoring the outcome of therapy on metastatic bone lesions.

Several markers of bone metabolism have been employed in studies of this kind. Among those employed are osteocalcin, C-terminal peptide of type I procollagen (PICP), N-terminal peptide of type III procollagen (PIIINP), pyridinoline cross-linked C-terminal peptide of procollagen I (ICTP), and bone-specific alkaline phosphatase (BA-1p). Bloomqvist et al. (1996) found that ICTP and PICP levels correlated with that of osteocalcin, but not with urinary or serum calcium. All three markers correlated with the number of metastases detected by bone scans.

The aminobisphosphonate ibandronate has marked osteoclast inhibitory activity and has been investigated as a treatment modality for metastatic bone disease and cancer-induced hypercalcemia. In combination with taxol/taxotere, ibandronate appears to be able to inhibit invasion of the bone by the human breast cancer cells MDA-MB231 (Magnetto et al. 1999) and the development of bone lesions in animals injected with myeloma cells (Dallas et al. 1999). Ibandronate markedly affects bone resorption in metastatic bone disease (Coleman et al. 1999). Osteocalcin, PICP, and BA-1p have been found to be reliable dose-dependent markers in a phase II clinical trial with ibandronate treatment of metastatic breast cancer. They were also found to be suitable for monitoring the effects of treatment of osteoporosis (Schlosser and Scigalla, 1997). However, Bombardieri et al. (1997) seem to disagree that any of these markers can replace bone scans.

So far as prostate cancer is concerned, ICTP has been reported to reflect bone metastasis more accurately than other markers, including PSA (prostate-specific antigen). Osteocalcin showed no correlation with metastatic spread (Maeda et al. 1997). In another study, PICP and BA-1p were found to increase with progression as indicated by bone scans. A slight increase in osteocalcin was also reported in patients with remission of metastatic bone lesions, but not related to progression (Koizumi et al. 1995). Obviously more clinical trials are needed to arrive at any firm conclusions. This need is underlined by laboratory work on the differentiation of osteoblastic cells, using conditioned media of the human prostatic carcinoma PC-3 cells and cell extracts. The effects of the conditioned medium have been studied on two osteoblastic cell lines, namely, a primary cell line derived from foetal rat calvaria and a rat osteosarcoma cell line ROS 17/2.8. The conditioned medium inhibited bone nodule formation in both cell lines without affecting cell proliferation. The conditioned medium also inhibited osteocalcin mRNA but not that of osteopontin (Kido et al. 1997). These data suggest there might be other factors involved in the formation of bone metastasis.

A development with much promise is the use of toxic gene therapy for cancer, with osteocalcin promoter for targeting the expression of the toxic gene in the treatment of tumours of osteoblastic lineage and metastatic tumours. Ko (1996) made an adenovirus construct with the TK gene under the control of an osteocalcin promoter (Ad-OC/TK). When this viral construct was introduced into cells of osteoblastic lineage, e.g., murine ROS cells and human MG-63 cells, the TK gene was expressed. In contrast, no TK expression occurred in nonosteoblastic cell lines. The addition of acyclovir (ACV) caused cell death in vitro. Similar growth inhibition and cytotoxicity were encountered in vivo when the adenovirus construct was injected into murine ROS osteosarcoma followed by intraperitoneal injection of ACV. (Cheon et al. 1997) has extended its findings and has reported that the administration of the Ad-OC/TK construct coupled with methotrexate was highly efficacious in the treatment of osteosarcoma. Shirakawa et al. (1998) adopted this strategy in another experimental tumour model. They introduced ROS rat osteosarcoma cells into nude mice by intravenous route. These cells formed tumour nodules in the lung. They then injected the Ad-OC/TK construct into the tail vein with subsequent intraperitoneal ACV treatment. This treatment markedly reduced the number of tumour nodules in the lungs and significantly enhanced survival. Furthermore, the cell-type specificity of the functioning of this construct was also demonstrated by Shirakawa et al. (1998). They constructed the adenovirus vector with RSV (Rous sarcoma virus) promoter, rather than by osteocalcin promoter, and placed the E. coli p-galactosidase gene under its control. When this construct was used, there was no osteoblast-specific expression of the p-galactosidase gene, but it was expressed nonspecifically in lung parenchyma.

This constitutes a rather elegant demonstration of cell-type-specific targeting of gene therapy coupled with cytotoxic drugs and certainly deserves further testing using experimental models of spontaneous metastasis.

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