BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia

BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia.BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

C‐terminal agrin fragment as a biomarker of muscle wasting and weakness: a narrative review

Abstract Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and cardiovascular and pulmonary diseases. This progressive loss of muscle mass and function may also result in the insurgence of a clinical syndrome termed sarcopenia, exacerbated by inactivity and disease. Sarcopenia and muscle weakness yield the risk of falls and injuries, heavily impacting on health and social costs. Thus, screening, monitoring and prevention of conditions inducing muscle wasting and weakness are essential to improve life quality in the ageing modern society. To this aim, the reliability of easily accessible and non‐invasive blood‐derived biomarkers is being evaluated. C‐terminal agrin fragment (CAF) has been widely investigated as a neuromuscular junction (NMJ)‐related biomarker of muscle dysfunction. This narrative review summarizes and critically discusses, for the first time, the studies measuring CAF concentration in young and older, healthy and diseased individuals, cross‐sectionally and in response to inactivity and physical exercise, providing possible explanations behind the discrepancies observed in the literature. To identify the studies investigating CAF in the above‐mentioned conditions, all the publications found in PubMed, written in English and measuring this biomarker in blood from 2013 (when CAF was firstly measured in human serum) to 2022 were included in this review. CAF increases with age and in sarcopenic individuals when compared with age‐matched, non‐sarcopenic peers. In addition, CAF was found to be higher than controls in other muscle wasting conditions, such as diabetes, COPD, chronic heart failure and stroke, and in pancreatic and colorectal cancer cachectic patients. As agrin is also expressed in kidney glomeruli, chronic kidney disease and transplantation were shown to have a profound impact on CAF independently from muscle wasting. CAF concentration raises following inactivity and seems to be lowered or maintained by exercise training. Finally, CAF was reported to be cross‐sectionally correlated to appendicular lean mass, handgrip and gait speed; whether longitudinal changes in CAF are associated with those in muscle mass or performance following physical exercise is still controversial. CAF seems a reliable marker to assess muscle wasting in ageing and disease, also correlating with measurements of appendicular lean mass and muscle function. Future research should aim at enlarging sample size and accurately reporting the medical history of each patient, to normalize for any condition, including chronic kidney disease, that may influence the circulating concentration of this biomarker

Endoscopic tumor length should be reincluded in the esophageal cancer staging system: Analyses of 662 consecutive patients

Esophageal cancer represents the 6th cause of cancer mortality in the World. New treatments led to outcome improvements, but patient selection and prognostic stratification is a critical aspect to gain maximum benefit from therapies. Today, patients are stratified into 9 prognostic groups, according to a staging system developed by the American Joint Committee on Cancer. Recently, trying to better select patients with curing possibilities several authors are reconsidering tumor length as a valuable prognostic parameter. Specifically, endoscopic tumor length can be easily measured with an esophageal endoscopy and, if its utility in esophageal cancer staging is demonstrated, it may represent a simple method to identify high risk patients and an easy-to-obtain variable in prognostic stratification. In this study we retrospectively analyzed 662 patients treated for esophageal cancer, stratified according to cancer histology and current staging system, to assess the possible role of endoscopic tumor length. We found a significant correlation between endoscopic tumor length, current staging parameters and 5-year survival, proving that endoscopic tumor length may be used as a simple risk stratification tool. Our results suggest a possible indication for preoperative therapy in early stage squamocellular carcinoma patients without lymph nodes involvement, who are currently treated with surgery alone

Il carcinoma esofageo radioindotto: prognosi e trattamento

Radiation therapy following mastectomy for breast cancer and mediastinal irradiation for Hodgkin’s lymphoma increases the risk of second malignancies in the irradiated area. Previous studies demonstrated that the risk of esophageal cancer (EC) is moderately increased starting 5 years after radiation exposure. From 1980 to 2007 we observed 4400 patients with primary EC. 32 patients fulfilled the definition criteria for radiation induced carcinoma. We analyzed demographics, surgical treatment, postoperative morbidity, mortality and prognosis. Previous cancers had been: breast cancer in 17 patients, Hodgkin’s lymphoma in 9, thymoma in 1, myeloma in 1, lung cancer in 4. Median interval between previous radiotherapy and esophageal cancer was 19 years (5-34). Histology was Squamous Cell Carcinoma in 27 patients, adenocarcinoma in 5. At diagnosis clinical stage was III in 18 patients, stage IV in one. Cytoreductive treatment was performed in 10 patients. 15 received palliative therapy without resection. 17 (53%) patients underwent esophagectomy: 16 had R0 resection and one R2. Postoperative morbidity was 76% (13/17): pulmonary complications were 29%, cardiac arrhythmia occurred in 23,5% (in one patients was fatal), sepsis in 17% and chylous leakage in 11,7%. Postoperative mortality was 12% (2/17). In our experience of 1900 esophagectomies morbidity was 43% and mortality was 4,5%. Median survival after palliation was 5 months and after curative resection was 18; five patients are still alive. Radiation induced EC is associated with high risk of postoperative mortality and morbidity including major cardiac and pulmonary complications. Neoadjuvant treatment is often not feasible due to previous radiotherapy.

Could the Pittsburgh Severity Score guide the treatment of esophageal perforation? Experience of a single referral center.

Esophageal perforation (EP) is characterized by high morbidity and mortality. The Pittsburgh Severity Score (PSS) is a scoring system based on clinical factors at the time of EP presentation, intended to guide treatment. The aim of the study is to verify PSS usefulness in stratifying EP severity and in guiding clinical decisions