It is now well accepted that alterations of TRP expression and functions are responsible for the impairment of cellular signalling pathways involved in cancer growth, metastasis, and chemoresistance [
115]. In particular, dysregulations of TRPC, TRPM, and TRPV members have been mainly correlated with malignant growth and progression. For this reason, in recent years, many efforts have been spent to improve the knowledge about these channels and the ability to target them. Thus, they are considered promising tools to inhibit cancer progression and to ameliorate the diagnosis and overcome chemoresistance in cancer [
29,
116,
117,
118,
119].
Interesting findings indicate and suggest that TRP channels could also be useful as diagnostic, prognostic, and therapeutic markers in the clinical management of haematological malignancies.
Table 3. Expression and functions of TRP channels in leukaemia and lymphoma patients.
Cancer Type |
TRP |
Effects |
References |
ALL |
TRPC3 |
↓Glucocorticoid resistance |
[44] |
AML |
TRPM2 |
↓OS ↓Doxo-sensitivity |
[120] |
|
TRPV4 |
↑Chemotherapy efficacy |
[121] |
CLL |
TRPC1 |
OS |
[122] |
Lymphoma |
TRPM8 |
Prognostic |
[123] |
|
TRPM4 |
↓OS ↓PFS |
[124] |
In this regard, integrated methylome, transcriptome, and epigenetic analysis showed that the expression level of many genes is dysregulated in paediatric leukaemia, and among them, the presence of TRPC1, TRPC4, TRPC3, TRPM2, TRPM4, and TRPM8 also stands out. These TRP channels are repressed, and this indicates a reduced potential for cell–microenvironment interactions and apoptotic potential of the ALL cells [
38,
39]. In accordance with these data, the potential utility to add TRP as diagnostic tools is also confirmed by other studies. It has been found that TRPM4 is significantly overexpressed in diffuse large B-cell lymphoma (DLBCL), compared to normal germinal centre (GC) B cells and, in addition, it is more expressed in activated B-cell-like than in GC DLBCL [
124]. Moreover, Hirai et al. demonstrated that TRPM8 positive neoplastic cells are mostly present in post-GC neoplasms but not in pre-GC or in the majority of GC neoplasms, suggesting TRPM8 as a marker to discriminate and diagnose reactive plasmablasts and mature B-neoplasms [
123].
Finally, TRPM2 was found to be strongly upregulated in AML samples from patients with normal karyotypes or all AML mutational subgroups with respect to normal hematopoietic stem cells or common myeloid progenitor, suggesting the possibility to differentiate normal from neoplastic cells by using TRPM2 expression levels [
49].
The potential prognostic impact of TRP channels in haematological malignancies has been recently highlighted. In DLBCL, the negativity of TRPM4 expression significantly correlated with better overall survival (OS) and progressive-free survival (PFS), compared with TRPM4 strong intensity. TRPM4 positivity was also associated with higher lactate dehydrogenase levels, higher Eastern Cooperative Oncology Group (ECOG) score, and stage III-IV. In addition, TRPM4-positive DLBCL patients treated with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) protocol displayed worse survival, consistent with its expression [
124]. Moreover, a close relationship between TRPM8 and International Prognostic Index (IPI) scores was found in DLBCL patients, indicating that lower TRPM8 expression levels are associated with higher IPI scores [
123].
In vivo studies underline the importance of developing new pharmacological approaches based on the targeting of TRP channels. In fact, mice injected with TRPM2-depleted leukaemia cells showed significantly reduced leukaemia, compared to controls, suggesting that these channels play an important role in leukemogenesis [
49]. The targeting of TRP channels has been shown to affect leukaemia cells and the tumour microenvironment. It has been recently demonstrated that TRPV4, by acting as a volume receptor, is involved in bone marrow adipocyte remodelling in AML mice, and it is clear that the inhibition of this remodelling increases the survival in the AML mouse model [
121].
Moreover, many in vitro studies, performed in patient-derived cells, demonstrated the ability of TRP-targeting therapy to inhibit cell proliferation and improve the effects of traditional chemotherapy in haematological malignancies. For instance, the TRPC3 channel blocker, Pyr3, enhances apoptosis induced by dexamethasone in ALL cells isolated from patients by altering calcium signalling, mitochondrial membrane potential, and ROS production [
44]. In addition, the activation of TRPV1, by using the specific agonist RTX, reduced cell proliferation, blocked cell cycle, and increased apoptosis in T cells from ALL patients [
37].
Obviously, further studies are necessary in order to develop and use drugs capable of modulating the TRP functions. However, interesting assumptions are gradually emerging. In fact, by molecular imaging methods, the in vivo potential of soricidin-derived peptides in targeting TRPV6-rich tumours has been evaluated [
125]. In addition, an apoptosis-inducing TRPV1 nanoagonist containing semiconducting polymer nanoparticles (SPNs) as nanocarriers and CPS as the agonist has been developed to target TRPV1-positive cancer cells [
43]. Finally, given that ongoing clinical trials specifically targeting TRPM4 have been approved in patients with stroke [
126], it can be expected that, soon, other TRP-based therapeutic strategies may have an adequate safety profile and be applied in the field of cancer, including haematological malignancies.