Primary melanoma tumor inhibits metastasis through alterations in systemic hemostasis

Abstract

Progression from a primary tumor to distant metastases requires extensive interactions between tumor cells and their microenvironment. The primary tumor is not only the source of metastatic cells but also can also modulate host responses to these cells, leading to an enhancement or inhibition of metastasis. Tumor-mediated stimulation of bone marrow can result in pre-metastatic niche formation and increased metastasis. However, a primary tumor can also inhibit metastasis through concomitant tumor resistance-inhibition of metastatic growth by existing tumor mass. Here, we report that the presence of a B16F10 primary tumor significantly restricted numbers and sizes of experimental lung metastases through reduction of circulating platelets and reduced formation of metastatic tumor cell-associated thrombi. Tumor-bearing mice displayed splenomegaly, correlated with primary tumor size and platelet count. Reduction in platelet numbers in tumor-bearing animals was responsible for metastatic inhibition, as restoration of platelet numbers using isolated platelets re-established both tumor cell-associated thrombus formation and experimental metastasis. Consumption of platelets due to a B16F10 primary tumor is a form of concomitant tumor resistance and demonstrates the systemic impact of a growing tumor. Understanding the interplay between primary tumors and metastases is essential, as clarification of concomitant tumor resistance mechanisms may allow inhibition of metastatic growth following tumor resection. Key messages Mice with a primary B16F10 tumor had reduced metastasis vs. mice without a primary tumor. Tumor-bearing mice had splenomegaly and fewer platelets and tumor-associated thrombi. Restoring platelets restored tumor-associated thrombi and increased metastasis. This work shows the impact that a primary tumor can have on systemic metastasis. Understanding these interactions may lead to improved ways to inhibit metastasis.

Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells

“…A study by Kirstein and colleagues showed reduced experimental metastases in mice bearing a primary B16F10 tumor (compared with controls without a primary tumor), but this was attributed to a reduction of circulating platelets and reduced formation of metastatic tumor cell-associated thrombi (38). Mice in that study developed splenomegaly (correlated with primary tumor size), which we did not observe in our experiments.…”

Multimodality cellular and molecular imaging of concomitant tumour enhancement in a syngeneic mouse model of breast cancer metastasis

“…We found splenomegaly in tumour-bearing mice however, this finding was associated with a reduction in red pulp and not differences in white pulp. Kirstein et al ., found splenomegaly in tumour-bearing animals was associated with tri-lineage extramedullary hematopoiesis as well as a reduction in white pulp in their mouse model of CTR 14 . Other groups have also seen splenomegaly in tumour-bearing animals, specifically in the 4T1-model.…”

“…Clinical and experimental evidence suggests that a primary tumour can both accelerate (CTE) or retard (CTR) the growth of distant metastases 4 – 14 . In this study, we found CTE effects in the syngeneic 4T1 model using multimodality imaging.…”

“…However, in the clinic, very few examples of CTE have been reported with most of them being related to suspected regressions of hepatic and/ or pulmonary metastases following nephrectomy for renal cell carcinoma 9 – 12 . While imaging has been used to describe CTR/CTE effects in patients 13 , the majority of studies evaluating CTR/CTE in preclinical models have relied on endpoint histological evaluation of tumour burden 14 , 15 . The application of cellular and molecular imaging tools will allow the non-invasive and longitudinal visualization of metastatic progression to study CTR/CTE effects in vivo , which will ultimately yield better evaluation of putative molecular mechanism(s) by which this physiological inhibition and/or enhancement occurs.…”

C-X-C Motif Ligand 1 (CXCL1) from melanoma cells down-regulates the invasion of their metastatic melanoma cells

“…There are clinical reports that distant metastases developed immediately after the removal of primary melanomas [ 4 , 5 ], suggesting that the metastatic process might be controlled by the primary tumor. The potential of a primary melanoma to inhibit the development of distant metastases has also been discussed based on experimental evidence [ 6 – 8 ]. Kirstein et al reported that the presence of B16F10 melanoma cells significantly restricted the numbers and sizes of experimental lung metastases [ 6 ].…”