Scientists at São Paulo State University (UNESP) in Brazil, along with colleagues from the University of Southern Denmark, and the University of Antioquia’s Medical School in Colombia, say they have analyzed 12 types of cancer and identified patterns of tumor protein secretion that correlated with the prevalence of cachexia and average weight loss for each type. Their study “The expression landscape of cachexia‐inducing factors in human cancers,” appears in the Journal of Cachexia, Sarcopenia and Muscle.

Robson Francisco Carvalho and his team
Robson Francisco Carvalho and his team at IBB-UNESP established a gene expression profile associated with cachexia. [Robson Francisco Carvalho]

According to Robson Francisco Carvalho, PhD, a professor at UNESP’s Botucatu Institute of Biosciences (IBB), cachexia is most frequent in patients with pancreatic, esophageal, colorectal, stomach, and head-and-neck cancer, and least frequent in patients with breast and prostate cancer.

“Cachexia-inducing factors, mainly deriving from cancer, had already been associated with development of the syndrome but it was not yet possible to link them to this variation in its prevalence and severity,” he said. “In the case of cancer of the pancreas, for example, which correlates closely with cachexia, we found alterations in the expression of 14 out of 25 genes that encode cachexia-inducing factors. In prostate cancer, which does not, we found no change in the expression of any of these 25 genes.”

“Cachexia is a multifactorial syndrome highly associated with specific tumor types, but the causes of variation in cachexia prevalence and severity are unknown. While circulating plasma mediators (soluble cachectic factors) derived from tumors have been implicated with the pathogenesis of the syndrome, these associations were generally based on plasma concentration rather than tissue‐specific gene expression levels. Here, we hypothesized that tumor gene expression profiling of cachexia‐inducing factors (CIFs) in human cancers with different prevalence of cachexia could reveal potential cancer‐specific cachexia mediators and biomarkers of clinical outcome,” write the investigators.

“…we combined uniformly processed RNA sequencing data from The Cancer Genome Atlas and Genotype‐Tissue Expression databases to characterize the expression profile of secretome genes in 12 cancer types (4651 samples) compared with their matched normal tissues (2737 samples). We systematically investigated the transcriptomic data to assess the tumor expression profile of 25 known CIFs and their predictive values for patient survival. We used the Xena Functional Genomics tool to analyze the gene expression of CIFs according to neoplastic cellularity in pancreatic adenocarcinoma, which is known to present the highest prevalence of cachexia.”

“A comprehensive characterization of the expression profiling of secreted genes in different human cancers revealed pathways and mediators with a potential role in cachexia within the tumor microenvironment. Cytokine‐related and chemokine‐related pathways were enriched in tumor types frequently associated with the syndrome. CIFs presented a tumor‐specific expression profile, in which the number of upregulated genes was correlated with the cachexia prevalence (r2: 0.80; P value: 0.002) and weight loss (r2: 0.81; P value: 0.002). The distinct gene expression profile, according to tumor type, was significantly associated with prognosis (P value ≤ 1.96 E‐06). In pancreatic adenocarcinoma, the upregulated CIF genes were associated with tumors presenting low neoplastic cellularity and high leucocyte fraction and not with tumor grade.”

“Our results present a biological dimension of tumor‐secreted elements that are potentially useful to explain why specific cancer types are more likely to develop cachexia. The tumor‐specific profile of CIFs may help the future development of better targeted therapies to treat cancer types highly associated with the syndrome.”

This initial analysis identified new factors that were specific to each type of tumor and could potentially explain variations in the prevalence and severity of cachexia in cancer. Data on all cellular protein-encoding genes came from the Human Protein Atlas. A total of 2,933 human genes associated with proteostasis have been described to date.

After analyzing the genes for their list of proteins, the researchers focused on investigating the genes that encode the 25 growth factors and cytokines known to be cachexia-inducing factors. These include CXCL8, IL1B, LIF, TGFA and IL6, analyzed in a previous study based on blood samples from cachectic patients with pancreatic cancer.

“In this manner we identified major correlations between the expression profiles of cachexia-inducing factors specific to each tumor type and the prevalence of the syndrome and average weight loss in patients with these cancers,” noted Carvalho. In pancreatic cancer, for which the patient survival rate is low, average weight loss is 13.7 kilograms (kg). In prostate cancer, which has a high survival rate, average weight loss is less than 2 kg. “We also identified major correlations between the expression profiles of cachexia-inducing factors for each type of tumor and a worse patient prognosis [lower survival rate],” he noted.

Patients with end-stage (refractory) cachexia are expected to survive for less than three months.

The genes described in the article have the potential to serve as biomarkers of the risk of developing cachexia, a complex condition whose treatment continues to defy science. “This suggests each type of tumor requires specific treatment against cachexia,” Carvalho said. “Knowledge of this profile can help physicians identify patients with an unfavorable prognosis, which influences important decisions about their treatment.”

The researchers at IBB-UNESP had previously made a key discovery in this connection. “Last year, while analyzing cachexia in cases of lung cancer, we found that the protein IL8 secreted by the tumor can induce muscle cell atrophy,” Carvalho added.

Conducted in collaboration with the Danish research group and with The São Paulo Research Foundation’s (FAPESP) support, the previous study was published in the journal Cancers. “Our analysis of secreted protein gene expression in the tumors of patients with lung cancer and low muscularity as assessed by computed tomography also identified a set of molecules that can be used for prognosis prediction,” explained Carvalho.

Practical application of this knowledge remains a challenge. “Having identified this set of biomarkers of cachexia with significant prognostic value, we may be able in future to develop a panel for assessment of the expression of these genes in tumor tissue,” said Paula Paccielli Freire, who conducted the investigation while researching for a PhD at IBB-UNESP.

The researchers are now analyzing the transcriptomes of individual cells in tumors with a high prevalence of cachexia, using a technique known as single-cell RNA sequencing. Transcriptome analysis was possible hitherto only with samples of tumor mass, which contains a complex mixture of various cell types.

“With the advance of single-cell RNA sequencing, we’re now able to identify exactly which cell secretes which cachexia-inducing factor,” according to Carvalho.

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