Cancer cells can either shrink or super size to enable survival

1st February 2023

A study has revealed how cancer cells either shrink or super size during drug therapy or other environmental challenges to enable survival

In a study published in Science Advances, researchers from the Institute of Cancer research in London, have identified how cancer cells can either shrink or become super sized as a means of survival, in the face of drug treatment or any other challenges that might occur within their environment.

Although it is acknowledged that there are differences in the size of cell types, there is also a recognition that for proliferating cell types, there is little variation in cell size. This implies that there is some mechanism or checkpoint, responsible for ensuring that cells maintain a particular size during the proliferative phase. Clearly, this checkpoint is disturbed in cancer and it is known that cancers will arise due to the accumulation of mutations in genes and which alter the normal proliferation, differentiation and death process.

In the current study, researchers used a combination of biochemical profiling and mathematical analyses, to examine how genetic changes affect the size of cancer cells. They focused on skin melanoma cells which are known to be driven by two genetic mutations, a BRAF gene (60%) and an NRAS mutation (20 – 30%) and examined differences in the size and shape of these cells with the two mutations.

Interestingly, the team found that BRAF-mutant cancer cells were very small, whereas NRAS-mutant cells were much bigger and larger still, when the cells were drug resistant. It seemed that small cells were able to better tolerate DNA damage, due to high concentrations of DNA repair proteins such as PARP, BRCA1 or ATM1.

The researchers believed that their findings might help clinicians to decide upon the choice of treatment. For instance, small cells were likely be more vulnerable to PARP inhibitors, i.e., drugs affecting the proteins responsible for DNA repair. In contrast, the larger NRAS-mutant cells, already had lots of DNA damage, which the cells were unable to repair and hence unlikely to respond well to PARP inhibitors, whereas immunotherapy might be a better option. The team think that both the BRAF and NRAS mutations may cause changes in cell size by affecting levels of a protein known as CCND1, which is involved in cell division, growth and maintenance of the cytoskeleton, as well as its interactions with other proteins.

Commenting on the study, lead author, Professor Chris Bakal, from the Institute of Cancer research, said ‘Cancer cells can shrink or grow to enhance their ability to repair or contain DNA damage, and that in turn can make them resistant to certain treatments.’ He added that the study had a potential diagnostic value. For instance, ‘by looking at cell size, pathologists could predict whether a drug will work, or if the cells will be resistant. In the future, it might even be possible to use AI to help guide the pathologist, by making a rapid assessment about the size of cells and so the treatments that are most likely to work.’

Higher fish intake associated with increased risk of melanoma

15th June 2022

A large prospective cohort study found that a higher fish intake was linked with an increased risk of both malignant and in situ melanoma

A higher fish intake appears to be associated with a greater risk of developing both malignant and in situ melanoma according to the results of a prospective cohort study by a group of US researchers.

Melanoma of the skin is the 17th most common cancer worldwide and in 2020, there were an estimated 325 000 new cases and 57 000 deaths. Although a family history and sun exposure have become well recognised as risk factors for the development of a melanoma, dietary factors may also play an important role. For example, caffeine intake may have beneficial and protective effects against cutaneous malignant melanoma, while higher citrus fruit intake and alcohol consumption may have a detrimental effect. Furthermore, while some data point to a diet rich in omega-3 fatty acids as being protective against melanoma, other work has found no such beneficial effect. However, one study has suggested that a higher fish intake is associated with a higher risk of melanoma though the data supporting this was not provided in the paper.

For the present study, the US team used data generated by the US National Institute of Health (NIH)-AARP Diet and Health Study and sought to determine the relationship between a higher fish intake, as well as the type of fish and the risk of melanoma. The NIH-AARP cohort study collected data on fish intake as part of a food-frequency questionnaire and which was differentiated as fried fish, fish sticks, non-fried fish or sea-food and canned tuna. For the present study, the researchers determined the total fish intake as the sum of fried fish, non-fried fish and tuna intake. Using regression analysis, the researchers adjusted for several factors such as body mass index, age, gender, family history of cancer etc and categorised total fish into in quintiles, with the first quintile representing < 5.6 g/fish/day and the fifth > 28.3 g/fish/day.

Higher fish intake and the development of melanoma

A total of 491,367 individuals with a median baseline age of 62 years (59.6% male) were followed for a median of 15.5 years. During the period of follow-up, there were 5,034 cases of malignant melanoma and 3,284 melanoma in situ.

In fully adjusted models, when comparing the lowest to highest intake of fish, there was a significantly increased risk for malignant melanoma (Hazard ratio, HR = 1.22, 95% CI 1.11 – 1.35) and for melanoma in situ (HR = 1.28, 95% CI 1.13 – 1.44).

When analysing the type of fish, the risk of malignant melanoma was elevated for the highest intake of tuna (HR = 1.20) and non-fried fish (HR = 1.18) although there was significantly lower risk for the highest intake fried fish (HR = 0.90, 95% CI 0.83 – 0.98). This pattern was also true for melanoma in situ.

The authors suggested that these results could be explained by the contamination of fish by polychlorinated biphenyls, dioxins etc. While they could not offer any direct proof to support this hypothesis, there is some research which shows a  direct association between dietary polychlorinated biphenyls and risk of melanoma.

They concluded that future studies were needed to replicate these findings and to identify the components of fish responsible for the observed associations.

Citation
Li Y et al. Fish intake and risk of melanoma in the NIH-AARP diet and health study Cancer Causes Control 2022

Study shows immune checkpoint inhibitors combined with radiotherapy offers no survival benefit in melanoma

8th April 2022

Immune checkpoint inhibitors and radiotherapy offer no survival benefit in melanoma, although 12-month progression-free survival is improved, according to a study

A meta-analysis by researchers from Beijing Tongren Hospital, Capital Medical University, Beijing, China, has concluded that adding radiotherapy to immune checkpoint inhibitors (ICIs)for the treatment of patients with melanoma offers no overall survival benefit despite a significant improvement in 12-month progression-free survival.

According to the World Cancer Research Fund, melanoma is the 19th most commonly occurring cancer in men and women, with nearly 300,000 new cases reported in 2018. Among patients whose melanoma has undergone metastases, ICIs, monoclonal antibodies which target the programmed death cell protein 1 (PD-1), the programmed death-ligand 1 (PD-L1), or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), represent the standard of care. Nevertheless, while effective, when used as mono-therapy, ICIs produce an overall response rate ranging from 0% to 17%, though these figures increase to more than 33.3% when the agents are combined.

Radiotherapy is routinely used in treatment of solid cancers, such as hepatocellular carcinoma (HCC) and several preclinical and clinical studies have explored the efficacy of combining radiotherapy and ICIs in HCC and with promising outcomes. Moreover, a meta-analysis of 11 studies found that combining ICIs with radiotherapy showed better local efficacy than ICI mono-therapy for treating melanoma brain metastasis.

Despite this, few studies have systematically examined the combined effect of ICIs and radiotherapy in the treatment of patients with melanoma. For the present study, the Chinese team set out to summarise the efficacy of radiotherapy in combination with ICIs in the treatment of non-brain metastatic melanoma. They included all available trials such as single-arm and control studies in which the endpoints of overall response rate (ORR), overall survival (OS) or progression-free survival (PFS) were reported. The team used regression analysis and presented their results using odds ratios.

Immune checkpoint inhibitors and radiotherapy outcomes

After an extensive literature search, 9 articles (7 retrospective studies and 2 prospective cohort trials) involving 624 patients were identified and included in the analysis.

Combing radiotherapy with ICIs led to a higher ORR compared with ICIs alone (35% vs 20.4%, p = 0.004) However, in terms of OS, the 12-month odds ratio (OR) comparing the combination to ICI treatment alone was 1.83 (95% CI 0.32 – 5.52, p = 0.69) and hence not significantly different.

While there was no significant difference between the two treatment options in PFS at 6-months (OR = 0.53, 95% CI 0.26 – 1.08, p = 0.08), this difference became significant at 12-months (OR = 0.48, 95% CI 0.29 – 0.80, p = 0.005).

Commenting on these findings, the authors highlighted that with most studies being retrospective in nature and no randomised trials, there was a need for prospective trials to further explore the efficacy of combining radiotherapy with ICIs in melanoma.

They concluded that while, at present, there was no evidence of a survival benefit by combining the two therapies, an improvement in PFS was evident but further high quality trials were required to confirm these findings.

Citation
Yin G et al. Efficacy of radiotherapy combined with immune checkpoint inhibitors in patients with melanoma: a systemic review and meta-analysis Melanoma Res 2022