Migratory neighbors and distant invaders: tumor-associated niche cells

Abstract

The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.

Figure 1.

Stromal cell recruitment at primary and metastatic sites. (A, top left) Early-stage stromal cell recruitment at the primary tumor includes immune infiltrates such as TEMs, TAMs, BMDCs (HPCs and EPCs), MDSC cells, and recruited CAFs. (Top middle) The production of matrix proteases and secretion of proangiogenic chemokines promotes local endothelial cell proliferation and chemotaxis. Blood vessel maturation is promoted via pericyte investment at vascular endothelium, although vessels remain leaky and disorganized. (Top right) Intravasation of tumor cells into the circulation, as well as invasion into surrounding tissue, is mediated by paracrine signaling exchange between fibroblasts, macrophages, and tumor cells. (B, bottom left) Stromal cell alterations at distant future metastatic organs include the activation of fibroblasts and the recruitment of HPCs and myeloid precursor cells. (Bottom middle) The secretion of inflammatory chemokines and matrix-degrading enzymes results in tumor cell adherence and proliferation at these sites. (Bottom right) Finally, the acquisition of blood supply via EPC and EC recruitment results in the progression of micrometastatic to macrometastatic disease.

Figure 2.

Niche-to-niche migration of BM and tumor cells. The transit of BM and tumor cells from their respective niches is a multidirectional pathway. Hematopoietic cells are mobilized from the BM niche in response to tumor-secreted chemokines and subsequently home to both the primary tumor microenvironment and peripheral niches. BMDCs homing to the primary tumor niche may remain in an undifferentiated state in the form of HPCs, EPCs, MSCs, or GR-1⁺ CD11b⁺ MDSCs; or may differentiate into more specialized cell types including TAMs. Early BMDCs in transit to premetastatic peripheral niches likely possess an undifferentiated status as HPCs or myeloid-precursor cells, and at later stages involve homing of EPCs. Metastasizing tumor cells subsequently travel to peripheral niches occupied by BMDCs.