Tumor cell-platelet interactions in vitro and their relationship to in vivo arrest of hematogenously circulating tumor cells

Abstract

Aggregation of rat platelets was induced in vitro by homologous rat Walker 256 carcinosarcoma cells and the extent of tumor cell-platelet interactions examined ultrastructurally. By 30s there was surface contact between unstimulated platelets and tumor cell microvilli. By midphase aggregation (2-3 min) tumor cells became enmeshed within expanding platelet aggregates. Tumor cell microvilli and platelet pseudopodia interdigitated as aggregation progressed. During the later stages of aggregation (6-10 min) tumor cells formed large processes which penetrated deep into the aggregate. Platelet activation (i.e. degranulation) occurred in gradient fashion and was concentrated near tumor cell membrane sites involved in process formation. At these later stages tumor cells near the aggregate periphery were found to have engulfed platelets or platelet fragments. Tumor cell-platelet interactions in the pulmonary microvasculature were also studied in vivo following injection of murine Lewis lung carcinoma, 16C mammary adenocarcinoma, and B16 amelanotic melanoma tumor cells into the tail vein. Platelets demonstrated a biphasic association with arrested tumor cells with peak interactions occurring at 10-30 min and 4-24 h. Ultrastructurally, tumor cells exhibited newly formed processes which interdigitated with the platelet aggregate. Such processes formed only in areas of contact with platelets and not in areas of contact with endothelial cells or other blood elements (i.e. erythrocytes, polymorphonuclear leukocytes). Numerous tumor cell mitochondria were concentrated in the areas of greatest platelet-tumor cell process activity. At early time intervals (2-10 min), intravascular platelet degranulation was observed primarily in platelets associated with tumor cell processes. Tumor cells also were found to have engulfed platelet fragments in vivo.

Tumor-elicited polymorphonuclear cells, in contrast to "normal" circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells.

“…These signals come from either other tumor cells or the host. For example, tumor cells can collaborate to increase the efficiency of arrest in the microvasculature by forming homotypic emboli (27,28) or heterotypic emboli with platelets and/or lymphocytes (1,3,29). Others (30,31) have shown that the presence of neutrophils can enhance tumor cell adhesion to intimal components.…”

Platelets and cancer metastasis: A causal relationship?

“…In response to platelet aggregation and activation, tumor cells extended numerous newly formed processes which interdigitated with platelet aggregates [15][16][17]19], and which may represent tumor cell 'activation'. The development of the cellular processes depends on an intact tumor cell cytoskeleton network since disruption of tumor cell microfilaments (with cytochalasin) and intermediate filaments (with cycloheximide) but not microtubules (with colchicine) leads to blocked tumor cell association with platelets in vivo and platelet aggregation induced by tumor cells in vitro [20][21][22].…”

“…Our laboratories [15][16][17], using three morphologically distinct murine cell lines (i.e., B16a melanoma, Lewis lung carcinoma and 16C mammary adenocarcinoma), conducted extensive ultrastructural studies of tumor cell interaction with the microvasculature during a time range of 2 min to 192 h following intravenous tumor cell injection. We put special emphasis on the process of tumor cell arrest in the vasculature, potential tumor cell interactions (association) with platelets, leukocytes and EC, and tumor cell extravasation.…”

Indomethacin Inhibits the Accumulation of Tumor Cells in Mouse Lungs and Subsequent Growth of Lung Metastases

“…Following the arrest and attachment of tumor cells to endothelial cells, platelets rapidly associate with the arrested tumor cell [27][28][29], leading to the induction of endothelial cell retraction [30], spreading of tumor cells on the subendothelial matrix, release of proteases and finally cell migration through the subendothelial matrix [27,28]. Platelets are capable of synthesizing TxA 2 but not prostacyclin (PGI 2 ).…”