Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.
Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.
a Department of Research and Statistics , IRCCS Arcispedale Santa Maria Nuova , Reggio Emilia , Italy .
Adriana
A
Albini
b Scientific and Technology Park, IRCCS MultiMedica , Milan , Italy .
Antonino
A
Bruno
a Department of Research and Statistics , IRCCS Arcispedale Santa Maria Nuova , Reggio Emilia , Italy .
Cristina
C
Gallo
c Department of Hand Surgery , San Giuseppe MultiMedica Hospital of Milan , Milan , Italy .|d Department of Clinical Sciences and Community , Plastic Surgery School, University of Milan , Milan , Italy , and.
Giorgio
G
Pajardi
b Scientific and Technology Park, IRCCS MultiMedica , Milan , Italy .|e Department of Biotechnology and Life Sciences , University of Insubria , Varese , Italy.
Douglas M
DM
Noonan
a Department of Research and Statistics , IRCCS Arcispedale Santa Maria Nuova , Reggio Emilia , Italy .
Katiuscia
K
Dallaglio
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D059016:Tumor Microenvironment / Q000502:physiology*
Cancer initiating cells; cancer stem cells; connective tissue; heterogeneity; tumor microenvironment