The Balance Between Normal and Tumor Tissues in Phototherapy of Tissues Harboring Cancer

I n the photobiomodulation (PBM) session of the annual meeting of American Society for Lasers in Medicine and Surgery (ASLMS) in 2009, there was a consensus that low-level light (LLL) might have no effect on tumor growth. In the PBM session in 2012, Liu put forward that “there may be indirect PBM (iPBM) on tumor growth.” ¹ However, daily two-dimensional (2-D) tumor measurements by Myakishev-Rempel et al. demonstrated no measurable effect of red light at 670 nm from light-emitting diode array (RLED) on the tumor growth of ultraviolet induced SKH1 mouse nonmelanoma skin cancer. ² This commentary tried to provide an explanation of the contradiction.

Whether a PBM of an LLL on a function is a direct/indirect PBM depends upon whether the function and its subfunctions are normal/dysfunctional. ^3,4 During a direct PBM, an LLL may self-adaptatively modulate a dysfunctional function, but cannot directly modulate a normal function. During an indirect PBM (iPBM), an LLL may self-adaptively modulate a dysfunctional subfunction of a normal function until it is normal and then the normal function is upgraded. Most studies have been based on direct PBM, but the studies on iPBM were just beginning. The proliferation of highly metastatic human melanoma cell line A2058 in 10% fetus bovine serum is normal. Hu et al. irradiated the cells with an LLL and incubated them for 1–5 days. ⁵ They found that the LLL at 1.0 and 2.0 J/cm² promoted the normal proliferation 3 days after LLL treatment. They further found that LLL at 1.0 J/cm² immediately induced an increase in mitochondrial membrane potential, adenosine-5′-triphosphate, and 3′-5′-cyclic adenosine monophosphate via enhanced cytochrome c oxidase activity, promoted phosphorylation of Jun N-terminal kinase/activator protein-1 expressions, and increased expression of interleukin (IL)-8 and transforming growth factor (TGF)-β 1.

There may be an iPBM on tumor growth. ¹ Tumor growth is always normal. It is maintained by tumor growth-essential/nonessential subfunctions. The more normal tumor growth-nonessential subfunctions there are, the faster the tumor growth. Straussman et al. ⁶ developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs, and found that stromal cells produced hepatocyte growth factor that enhanced the proliferation of 45 cancer cell lines and helped the cancer cells resist chemotherapy treatment. There is at least one dysfunction in tumor cells, telomere dysfunction. Telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities. ⁷ Perera et al. found that telomere dysfunction acted in a tumor-suppressive mechanism. ⁸ In other words, the iPBM may self-adaptively modulate telomere dysfunction until it is normal, and then the tumor growth is upgraded. As Myakishev-Rempel et al. ² have cited, Revazova et al. ⁹ have studied the effect of an LLL on the growth of human gastric adenocarcinoma transplanted to athymic mice, and found that 33 day LLL shortened the latency of tumor growth and increased the size of their tumor node.

Myakishev-Rempel et al. have found a PBM on the ultraviolet-irradiated skin. ² They have delivered whole body phototherapy to the affected individual, rather than treating a specific area. Their qualitative observations of improvement in skin quality at early time points, which was mediated by iPBM of RLED on the skin, and relief of sickness behavior at later stages of the investigation, which was mediated by the direct PBM of RLED on the skin, suggested that RLED was capable of producing beneficial effects for the whole animal despite the presence of tumors. Ultraviolet exposure is associated with increased production of reactive oxygen species, ¹⁰ and then eukaryotic initiation factor 2α subunit activation. ^11,12 The oxidative stress in muscular contusion has been found to be self limited. ¹³ The ultraviolet-induced oxidative stress of the skin might be self limited at early time points so that RLED played an iPBM role, but the one became chronic at later stages of the investigation so that RLED played a direct PBM role.

The normal skin PBM and the tumor PBM might balance each other out. Matsumura et al. found that although 100% of wild type mice developed skin tumors after 45 weeks of ultraviolet irradiation, only 60% of CD1D-/- mice developed skin tumors. ¹⁴ CD1D presents glycolipid antigens to a unique subset of T cells, designated natural killer T (NKT) cells. ¹⁴ During ultraviolet carcinogenesis, there might be at least two distinct stages at which the CD1D gene product plays a role. One involves suppression of tumor rejection by NKT cells. ¹⁵ NKT cells are CD1D restricted, and CD1D-/- mice do not have functional NKT cells. ¹⁵ Kim et al. have found that IL-10 and TGF-β 1 production in vitro were reduced in cells from the spleen, and that Peyer's patches of CD1D-/- mice compared with those of control mice fed ovalbumin. ¹⁶ Finkelstein et al. have shown that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of amyotrophic lateral sclerosis, the levels of NKT cells increased dramatically, and hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, whereas the expression of IGF binding protein−1 was augmented by more than 20fold in mSOD1 mice relative to wild type animals. ¹⁷ Low intensity He-Ne laser irradiation could self-adaptively modulate the growth factors IGF-1 and TGF-β1 in muscular regeneration. ¹³ As a reasonable extension, RLED might inhibit NKT cells by modulating the growth factors IGF-1 and TGF-β1, and then resist tumor iPBM. This might be the reason for the small but statistically significant decrease in 2-D tumor area observed on days 16–23. ²

The normal tissue PBM and the cancer tumor PBM were fought out during the phototherapy of tissues harboring cancer, the outcomes of which may not be predictable. Further studies are warranted to gain a better understanding of this issue.