The mesenchymal tumor microenvironment: a drug-resistant niche

Abstract

Drug and radiation resistance represent a challenge for most anticancer therapies. Diverse experimental approaches have provided evidence that the tumor-associated microenvironment constitutes both a protective shell that impedes drug or radiation access and a permissive or promotive microenvironment that encourages a nurturing cancer (i.e., cancer stem cell) niche where tumor cells overcome treatment- and cancer-induced stresses. Better understanding of the effects of the tumor microenvironment on cancer cells before, during and immediately after chemo- or radiotherapy is imperative to design new therapies aimed at targeting this tumor-protective niche. This review summarizes some of the known mesenchymal stromal effects that account for drug resistance, the main signal transduction pathways associated with this resistance and the therapeutic efforts directed to increase the success of current therapies. Special emphasis is given to environment-mediated drug resistance in general and to cell adhesion-mediated drug resistance in particular.

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, 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. 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.

Figure 2. Activated stroma comprises a risk factor in non metastatic renal cell carcinoma. Multivariate CART-based sorting of a cohort where non metastatic patients (M0, Mx) were sorted by their stromal palladin expression levels representing non-activated (stromal palladin ≤ 0.75) vs. activated (stromal palladin > 0.75) stromal levels and were compared with metastatic patients (M ≥ 1) in a Kaplan-Meier curve showing time-scale (in months) at the x-axis and corresponding survival probability (e.g., survival fraction) at y-axis. The corresponding p values are provided. This figure was adapted from reference .