Macrophages and cancer

Abstract

The uncontrolled growth of metastases resistant to conventional therapeutic modalities is a major cause of death from cancer. Data from our laboratory and others indicate that metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. These metastases can be clonal in their origin, and different metastases can originate from different progenitor cells. In addition, metastatic cells can exhibit an increased rate of spontaneous mutation compared with benign nonmetastatic cells. These data provide an explanation for the clinical observation that multiple metastases can exhibit different sensitivities to the same therapeutic modalities. These findings suggest that the successful therapy of disseminated metastases will have to circumvent the problems of neoplastic heterogeneity and the development of resistance. Appropriately activated macrophages can fulfill these demanding criteria. Macrophages can be activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators. Tumoricidal macrophages can recognize and destroy neoplastic cells in vitro and in vivo, leaving nonneoplastic cells uninjured. Although the exact mechanism(s) by which macrophages discriminate between tumorigenic and normal cells is unknown, it is independent of tumor cell characteristics such as immunogenicity, metastatic potential, and sensitivity to cytotoxic drugs. Moreover, macrophage destruction of tumor cells apparently is not associated with the development of tumor cell resistance. Macrophages are found in association with malignant tumors in a definable pattern, suggesting that the most direct way to achieve macrophage-mediated tumor regression is in situ macrophage activation. Intravenously administered liposomes are cleared from the circulation by phagocytic cells, including macrophages, so when liposomes containing immunomodulators are endocytosed, cytotoxic macrophages are generated in situ. The administration of such liposomes in certain protocols has been shown to bring about eradication of cancer metastases. Macrophage destruction of metastases in vivo is significant, provided that the total tumor burden at the start of treatment is minimal. For this reason, we have been investigating various methods to achieve maximal cytoreduction in metastases by modalities such as chemotherapy or radiotherapy prior to macrophage-directed therapy. It is important to note that even the destruction of 99.9% of cells in a metastasis measuring 1 cm2 would leave 10(6) cells to proliferate and kill the host. The ability of tumoricidal macrophages to distinguish neoplastic from bystander nonneoplastic cells presents an attractive possibility for treatment of the few tumor cells which escape destruction by conventional treatments. Macrophage-directed therapy has been studied in several human protocols, yielding important biological information about the use of liposome-encapsulated macrophage activators in cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased primary tumor growth in mice null for β3- or β3/β5-integrins or selectins

“…The same could be true for their infiltration of tumors, and we do detect fewer macrophages infiltrating tumors growing in integrin-or selectin-deficient mice, although the numbers of circulating monocytes͞macrophages do not differ among the strains of mice (15). Macrophages have been suggested to be tumoricidal (36)(37)(38)(39), although other reports have suggested that they also can contribute to tumor growth (40-42); they probably have both effects (42)(43)(44)(45)(46).…”

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

“…The coated filters were prepared by using Matrigel suspensions at 250 μg/ml. B16 melanoma cells (25x10 3 ) suspended in 200 μl DMEM 4500 containing 250 μg/ml BSA were seeded in the upper chamber and incubated for 18-24 h. After incubation, cells on the upper side of the filters were wiped off and the membranes were fixed overnight in ice-cold methanol. Cells on the lower side of the membranes were stained with Diff Quick and counted.…”

“…Among the various types of host cells, tumor-associated macrophages (TAMs) play a critical role in tumor progression. Whereas TAMs may destroy tumor cells following their activation (3,4), they may also produce growth factors, cytokines and proteases that promote invasion and metastatic diffusion of tumor cells (5)(6)(7)(8)(9)(10)(11)(12)(13). It is of particular interest that the failure to recruit macrophages into the tumor microenvironment in colony stimulating factor-deficient (CSF op /CSF op ) mice reduced the metastatic spread of transplanted mammary cancer (14).…”

Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2

“…Aspects of tumor cells, such as deformibility (Sato and Suzuki, 1976), aggregation (Nicolson, 1986), and cell surface adhesion molecules (Hofmann et al, 1991;Frixen et al, 1991), and those of the host, such as blood turbulence (Sato and Suzuki, 1976;Weiss and Dimitrov, 1986), platelets (Sugimoto et al, 1987;Tsuruo et al, 1986), T-cells (Wiltrout et al, 1979), natural killer cells (Hanna and Fidler, 1980;Herberman, 1989), and macrophages (Fidler, 1985;Whitworth et al, 1990), all contribute to the destruction or survival of blood-borne tumor emboli. Moreover, the passage of tumor cells through capillaries leads to cell lysis by sheer force of movement (Sato and Suzuki, 1976;Weiss and Dimitrov, 1986) and by nitric oxide (NO) produced by cytokine-activated endothelial cells (Li et al, 1991a, b;Geng et al, 1996).…”