Isaiah J. Fidler

The Use of Activated Macrophages for the Destruction of Heterogeneous Metastasis

Metastasis, the spread of malignant cells from the primary tumor to distant sites, is the major cause of cancer mortality. Indeed, by the time many malignancies are diagnosed, metastases have already been established in a variety of sites distant from the primary tumor, making selective excision or destruction by irradiation or chemotherapeutic agents extremely difficult. Exacerbating the problem of treating metastatic disease is the fact that cancer cells in different metastases originating from the same primary tumor, and in some instances even different zones within the same metastatic nodule, may respond completely differently to treatment. For example, although new and highly promising chemotherapeutic agents have been developed, their overall effectiveness is hindered by the common occurrence of drug resistance due to the rapid emergence of drug-resistant tumor cell variants, which then populate drug-resistant metastases (1,2; see also Chapters 5 and 6).

Role of Macrophages in Host Resistance Against Tumors

The most devastating aspect of cancer is the propensity of malignant neoplasms to spread from their primary site of growth to distant organs where secondary tumors, metastases, can develop. Despite remarkable advances in aggressive adjuvant therapy and improvements in general patient care, most deaths of patients with solid cancers are caused by metastases. There are several reasons for the current failure to eradicate metastasis. First, by the time of surgical excision of the primary neoplasm, metastases may have already occurred. Second, even when metastases are diagnosed, their location and number may limit the effective dose of therapeutic agent that can be delivered to the lesion without being toxic to the host. Third, the most formidable obstacle to successful treatment of metastasis is the heterogeneous nature of malignant neoplasms and the rapid emergence of metastases that are resistant to conventional therapeutic regimens [1–3].