Neoplastic cells form only one part of a complex network of cell types that make up a breast tumor. The normal cell types that make up the nonneoplastic components of tumors include fibroblasts, endothelium, and inflammatory cells, such as tumor associated macrophages (TAMs). TAMs have the potential to carry out both anti- and protumor activities. In their antitumor role TAMs can present tumor antigens to cytotoxic T-cells and are capable of being directly cytotoxic to neoplastic cells. Conversely, TAMs are also able to promote tumor growth directly by secreting breast tumor mitogens, such as epidermal growth factor, and indirectly by stimulating tumor angiogenesis and metastasis. Recent studies have indicated that in breast cancers the protumor role of TAMs is dominant, and that TAMs may be executing a “wound healing” type of process in response to stimuli found in the tumor microenvironment, such as hypoxia. As such, TAMs may provide opportunities for future therapeutic interventions.

Tumor-associated macrophages in breast cancer.

Tailoring of chitosan through the involvement of its amino, acetamido, and hydroxy groups can give derivatives of enhanced solubility and remarkable anticancer activity. The general mechanism of such activity is associated with the disturbances in normal functioning of cell cycle, interference to the central dogma of biological system from DNA to RNA to protein or enzymatic synthesis, and the disruption of hormonal path to biosynthesis to inhibit the growth of cancer cells. Both chitosan and its various derivatives have been reported to selectively permeate through the cancer cell membranes and show anticancer activity through the cellular enzymatic, antiangiogenic, immunoenhancing, antioxidant defense mechanism, and apoptotic pathways. They get sequestered from noncancer cells and provide their enhanced bioavailability in cancer cells in a sustained release manner. This review presents the putative mechanisms of anticancer activity of chitosan and mechanistic approaches of structure activity relation upon the modification of chitosan through functionalization, complex formation, and graft copolymerization to give different derivatives.

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Anticancer Activity of Chitosan, Chitosan Derivatives, and Their Mechanism of Action

Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor

The functionalized dextrans termed carboxymethyl benzylamide sulfonate dextran (CMDBS) represent a family encompassing a wide range of polymers. These soluble macromolecular compounds, which are substituted with specific chemical functional groups, are designed to interact with living systems. By analogy with glycosaminoglycan heparin, a natural highly charged anionic polysaccharide that exerts a variety of biological effects, we postulated that CMDBS compounds also possess binding sites capable of specific interactions with biological constituents, depending on the overall composition of the polymer. The synthesis and heparin-like properties of these CMDBS have been extensively investigated. Thus, it appears that dextran derivatives can mimic the action of heparin in regard to its interactions with antithrombin and serine proteases involved in blood coagulation. Other derivatives interact with various components of the immune system or with adhesive proteins such as fibronectin in modulating the proliferation of Staphylococcus aureus. Because they are able to stimulate wound healing in various in vivo models, these polysaccharides may also constitute a family of tissue repair agents because of their protecting and potentiating effects with heparin binding growth factors. Moreover, dextran derivatives in contact with cells such as endothelial cells, smooth muscle cells, or tumoral cells can affect both cell proliferation and metabolism. It appears that these bioactive polymers are also efficient tools to investigate the precise mechanism of action of individual biological activities by contrasting their mode of action to that of heparin. In addition to their numerous biological properties and biospecificity, functionalized dextrans are relatively simple to manufacture and exempt of donor contaminant, which make them attractive in a variety of clinical applications.

Carboxymethyl benzylamide sulfonate dextrans (CMDBS), a family of biospecific polymers endowed with numerous biological properties: A review

Growth factor-induced angiogenesis is being investigated in ischemic heart disease. Intracoronary and intravenous delivery are the most practical, but are limited by low myocardial uptake and significant systemic recirculation. The pericardial space may act as a drug delivery reservoir with increased myocardial uptake and reduced systemic toxicities. This study was designed to investigate the myocardial and tissue deposition and retention of basic fibroblast growth factor (FGF-2) after intrapericardial administration in normal and chronically ischemic animals. Twelve Yorkshire pigs were used for the study [six normal and six animals with chronic myocardial ischemia (ameroid constrictor on LCx)] with bolus intrapericardial administration of (125)I-FGF-2 (25 micro Ci) with 30 micro g of cold FGF-2 and 3 mg of heparin. Tissue and myocardial distribution was determined at 1 and 24 hr by measuring (125)I-bFGF-specific activity. In addition, regional myocardial deposition was determined using (125)I-bFGF activity and organ level autoradiography. The heart (pericardium and myocardium) accounted for the majority of (125)I-bFGF activity in ischemic animals (30.9% at 1 hr and 23.9% at 24 hr). Left anterior descending artery territory activity/gm of tissue for nonischemic and ischemic animals was 0.01% and 0.01% at 1 hr and 0.0009% and 0.12% at 24 hr, respectively. LCx territory activity for nonischemic and ischemic animals was 0.006% and 0.008% at 1 hr and 0.03% and 0.05% at 24 hr, respectively. Endocardial activity was low at all time points. Liver uptake was 0.47% (nonischemic) and 0.34% (ischemic) at 1 hr and 0.23% (nonischemic) and 0.54% (ischemic) at 24 hr. Intrapericardial delivery of FGF-2 provides markedly higher myocardial deposition and retention and lower systemic recirculation than intracoronary or intravenous delivery at the expense of poor subendocardial penetration. This limitation, however, did not affect its efficacy.

Intrapericardial administration of basic fibroblast growth factor: Myocardial and tissue distribution and comparison with intracoronary and intravenous administration

Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells.

The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7)

Inhibition of human breast epithelial HBL100 cell proliferation by a dextran derivative (CMDB7) with the FGF2 autocrine loop

The highly tumorigenic human breast cancer MCF-7ras line (Ha-ras-transfected MCF-7 cell line) loses estrogen dependence and secretes diffusible growth factors that support its own tumor growth in vivo. Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) inhibits the growth of breast MCF-7 and MCF-7ras cell lines. In this study, we have shown that conditioned medium (CM) from MCF-7 and MCF-7ras cells stimulated the DNA synthesis of BALB/c3T3 fibroblasts and that CMDB7 strongly inhibited these mitogenic effects in a dose-dependent manner. Neutralizing antibodies against platelet-derived growth factor (PDGF) partially inhibited the mitogenic effect of MCF-7ras CM. The flow cytometry analysis of the cell cycle showed that the CM of tumor cells increased the percentage of fibroblasts in S phase and that CMDB7 blocked them in G0/G1 phase. CMDB7 inhibited the mitogenic effect of PDGF-BB and transforming growth factor (TGF) beta1 but not those of epidermal growth factors and insulin-like growth factor on BALB/c3T3 fibroblasts. CMDB7 increased the electrophoretic mobility of radiolabeled PDGF-BB and TGF-beta1, apparently by forming a stable complex with these factors. On intact BALB/c3T3 fibroblasts, binding of iodinated growth factors (125I-TGF-beta1 and 125I-PDGF) to their receptors was completely displaced by CMDB7. In vivo studies demonstrated that s.c. injection of CMDB7 inhibited by 66% the tumor growth of MCF-7ras xenografts in nude mice. These results showed that CMDB7 inhibits the mitogenic effect of growth factors released from MCF-7 and MCF-7ras cells and suppresses tumor growth in the MCF-7ras model.

http://cgd.aacrjournals.org/cgi/reprint/9/6/497.pdf

Inhibition of MCF-7ras tumor growth by carboxymethyl benzylamide dextran : Blockage of the paracrine effect and receptor binding of transforming growth factor β1 and platelet-derived growth factor-BB

Erratum: Inhibition of human breast epithelial HBL100 cell proliferation by a dextran derivative (CMDB7): Interference with the FGF2 autocrine loop (Biochemical and Biophysical Research Communications (1997) 239 (424-428))

Jean François Morère

Papers

The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7)

Inhibition of human breast epithelial HBL100 cell proliferation by a dextran derivative (CMDB7) with the FGF2 autocrine loop

Inhibition of MCF-7ras tumor growth by carboxymethyl benzylamide dextran : Blockage of the paracrine effect and receptor binding of transforming growth factor β1 and platelet-derived growth factor-BB

Erratum: Inhibition of human breast epithelial HBL100 cell proliferation by a dextran derivative (CMDB7): Interference with the FGF2 autocrine loop (Biochemical and Biophysical Research Communications (1997) 239 (424-428))