Tumor acidosis
Upregulated glucose metabolism, as a consequence of increased
lactate and H+ extrusion from anaerobic glycolysis,
even in presence of sufficient oxygen ("Warburg
effect"), associated with acidification of the extracellular
space (pHe 6.2-6.8) is one of the major features of cancer.
However, tumor cells are well adapted to acidic
microenvironments, since they rely on proton exchangers and
transports, which exports protons to the microenvironment.
Several pH regulators are therefore involved in preserving such
pH homeostasis, including ATPases, Na+/H+
exchangers (NHEs), monocarboxylate transporters (MCTs) carbonic
anhydrases (CAs) and anion exchangers (AEs). Moreover, tumor
acidification (or tumor acidosis) has been associated with key
features of cancer aggressiveness, including invasion, increase
angiogenesis and resistance to therapy and evasion from the
immune system.
It is becoming increasingly evident that
extracellular acidosis could be targeted to block tumor
proliferation using for example proton pump inhibitors, which are
first responsible of H+ exporting mechanism. Even more
important is that changes in the level of acidosis can be used as
a marker of therapeutic response. As a consequence, novel imaging
approaches are urgently needed for non-invasively assessing the
efficacy of novel anticancer therapies.
To date,
imaging-based methods are commonly used in clinical settings to
assess glucose metabolism (using FDG-PET), providing a formidable
tool for evaluating treatment response. However, significant
shortcomings of FDG-PET approach are related to radiation
exposure (limiting repeated exams in a single individual) and to
radioactive compound 18F production (local cyclotron
owing to the short half-life) which cannot be found in every
hospital. Conversely, an effective imaging method that allows to
quantify extracellular tumor pH and to assess pHe related changes
following therapeutic treatment is still missing.
Other
imaging-based approaches, namely magnetic resonance spectroscopy
(MRS) and imaging (MRI) have been investigated. However, none of
them has shown feasibility to provide pHe maps with sufficient
spatial resolution and pH accuracy and to be easily translated
into clinical settings.
Recently, MRI-CEST (Chemical
Exchange Saturation Transfer) based methods for measuring pHe
with improved accuracy, concentration-independence and spatial
resolution have been proposed and investigated in preclinical
tumor models (Longo D et al., Cancer Research 2016, 76, 6463).
Consequently, MRI-CEST pH imaging can play a role as an
alternative to FDG-PET to characterize tumor metabolism and for
assessing treatment response.
Within our center we
have developed several
CEST-based pH sensors
for the non-invasive assessment of tumor pH. Among them, clinical
approved radiographic contrast agents such as
Iopamidol, iobitridol and iodixanol
have been exploited for measuring tumor pHe in murine tumor
models. Moreover, we have investigated lanthanide
PARACEST complexes (Yb-HPDO3A)
to measure extracellular pH.
We are interested to
assess:
- the relationship between tumor acidosis and glucose uptake,
- the role of tumor acidosis in cancer progression and invasion,
- tumor pHe imaging as a biomarker of treatment response to novel anticancer therapies.
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