Abstract
Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment.
Highlights
Solid tumors are composed of cancerous and non-cancerous cells
Various hematopoietic populations exist in tumor stroma Using the Lewis lung carcinoma (LL2) implantation mouse model, we characterized the hematopoietic compartment in the tumor stroma
Shown are the repopulation activities of hematopoietic populations derived from the cancer stroma in long-term reconstitution (n = 6) and secondary reconstitution experiments (n = 5). (E–F) Donor repopulation in T lineage (CD3), B lineage (B220), and myeloid lineage (Mac-1/Gr-1) in peripheral blood in the experiment described in panel D at 7 months post-transplant (n = 6). (G) Hematopoietic cells in tumor stroma originate from host bone marrow (BM). 1,000,000 CD45.1 donor BM cells were transplanted into lethally irradiated CD45.2 C57BL/6 mice
Summary
Solid tumors are composed of cancerous and non-cancerous cells. The non-cancerous cells, including endothelial cells, hematopoietic cells, fibroblasts, myofibroblasts, pericytes, and mesenchymal stem cells, collectively form the cancer stroma or microenvironment [1,2]. These stromal cells come from the local environment or from bone marrow (BM) via the circulation system and appear to provide important support for cancer cell growth and metastasis [1,2]. BM-derived cells are recruited to the cancer site to stimulate outgrowth of tumors and form angiogenic and pre-metastatic niches for cancer growth [3,4,5]. Since a tumor cannot develop without the parallel expansion of a tumor stroma, the lack of understanding of this cancer microenvironment has severely hampered cancer research and the development of effective therapeutic approaches
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