Figure 1. Stages during the development of environment-dependent drug resistance. (A) Homing or attraction. This first step requires specific cell-cell or cell-extracellular matrix interactions. Soluble stromal factors, such as SDF-1 and IL-6, and receptor-mediated adhesion contribute to attract tumor cells to the stromal niche where the tumor will be established. This first step is necessary in many hematopoietic malignancies,²⁷ as well as in the establishment of secondary (i.e., metastatic²⁸) tumors. Although homing is often seen in primary bone marrow tumors as well as in secondary tumor establishments, this step may not be necessary during primary solid tumor development. (B) De novo resistance. In this second stage (first stage for primary tumors that are not established in the bone marrow), the main stress from the treatment is applied to the, until then, drug naïve tumor. This step is characterized by a series of cell responses and the modification of the composition of the ECM creating a positive feedback loop that amplifies the pro-survival and anti-apoptotic signals. (C) Acquired resistance. This stage is commonly regarded as being environmental-independent, yet the microenvironment still plays an important role; for example, it can act as a barrier that physically or biochemically prevents the effective access of drugs to the tumor cells (see ref. 18 for review). Note the presence of a small amount of cancer resistance cells at early stages of development of drug resistance. This small cell population in what sometimes is regarded as the first stage (i.e., environment-dependent) and represents the possibility of a predisposed (i.e., cancer stem) resistant cell or, alternatively, one that has undergone a drug resistant mutation, will be selected during the stress period rendering a genetically different tumor signature compared with the drug naïve tumor population.