Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization

Abstract

Reciprocal interactions between neoplastic cells and their microenvironment are crucial events in carcinogenesis and tumor progression. Pervasive stromal reprogramming and remodeling that transform a normal to a tumorigenic microenvironment modify numerous stromal cells functions, status redox, oxidative stress, pH, ECM stiffness and energy metabolism. These environmental factors allow selection of more aggressive cancer cells that develop important adaptive strategies. Subpopulations of cancer cells acquire new properties associating plasticity, stem-like phenotype, unfolded protein response, metabolic reprogramming and autophagy, production of exosomes, survival to anoikis, invasion, immunosuppression and therapeutic resistance. Moreover, by inducing vascular transdifferentiation of cancer cells and recruiting endothelial cells and pericytes, the tumorigenic microenvironment induces development of tumor-associated vessels that allow invasive cells to gain access to the tumor vessels and to intravasate. Circulating cancer cells can survive in the blood stream by interacting with the intravascular microenvironment, extravasate through the microvasculature and interact with the metastatic microenvironment of target organs. In this review, we will focus on many recent paradigms involved in the field of tumor progression.

Fig. 1

Reciprocal interactions between stromal and cancer cells at primary site. Induction of a TM is driven by genetic instability of cancer cells, extrinsic stress stimuli; (hypoxia, aberrant microcirculation, acidosis, glucose deprivation, oxidative stress, pH changes) and intrinsic stressors (imbalanced cell growth, increased mutation rate, errors in glycoprotein and lipid biosynthesis and decreased amino acid supplies). Cancer cells develop adaptive strategies to overcome specific microenvironmental growth constraints. Stromal cells reprogramming, ECM remodeling and acquisition of an aggressive phenotype by cancer cells are crucial events in promoting intravasation, dissemination and metastasis

Fig. 2

Reciprocal interactions between cancer cells and intravascular and metastatic microenvironments. Establishment of metastasis at secondary sites requires several steps: (1) survival of CTCs in the intravascular microenvironment via interactions with circulating MDSCs, neutrophils and platelets, (2) initial arrest of CTCs by physical occlusion, (3) extravasation by TEM, (4) MET, establishment of a supportive premetastatic and metastatic niche, dormancy, (5) development of micro and macrometastasis and (6) self-seeding