Obesity and Stem Cells - Part V, Cancer
Over the past several blog posts, we have seen the significant negative effects of obesity. There are also differences between genders with regard to obesity; premenopausal women actually have a protection agains obesity compared to men and postmenopausal women; leukocyte and haematopoietic stem cells have different responses to obesity and these autonomous differences lead to an amplified response in males compared with females.(1) That is to say, “… immune system responses play a role in sex differences in metabolic disease” (p. 13261).
Rather than focus on the more often discussed topics within obesity or within stem cell biology, we have focused heavily upon the effects obesity has upon stem cell biology. We have focused on these important topics because they are rarely discussed but are critically important to understand. We have seen a significant display of crosstalk and feedback loops between adipose tissue and bone marrow cells and a host of other complexities. Today’s blog post is focused upon yet another interaction of obesity and adipose stem/stromal cells (ASCs) - cancer, cancer cells, and enhanced tumorigenesis by focusing on a review paper published by Strong et al (2015).(2) Why focus a blog in a series on obesity and stem cells directly onto the topic of cancer? The authors have a crucial comment in their conclusions that helps to answer this very question, “…ASCs altered by obesity, integrate into the tumor stroma and provide support for the growing tumor” (p. 324). That is, the impact of obesity on ASCs is powerful enough that obesity-related changes in ASCs support cancerous tumors.
In previous blog posts we saw some of the changes in a few growth factors and cytokines caused by obesity. For example, tumor necrosis factor-alpha (TNF-α) was discussed, in part, when outlining obesity-related inflammation. However, TNF-α has a role larger than inflammation; it plays an important role in “the adaptive response of the immune system, can induce fever, apoptosis (cell death), inflammation, and inhibiting tumorigenesis. However, dysregulation of TNF-α has been implicated in a variety of human disease, including cancer, because it activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, leading to the expression of a variety of inflammation-related genes…. Furthermore, long-term exposure of hormone receptor positive breast cancer cells to TNF-α induces an epithelial-to-mesenchymal transition (EMT), a process by which tumor cells, lose their cell-to-cell adhesion and gain migratory properties that facilitate metastasis” (p. 321). Studies have shown that ASCs from obese individuals promote breast cancer cell proliferation, angiogenesis, and metastasis. In this blog, we will use the Strong et al paper to outline how some of the dysregulation in various factors relate to cancer (Table 1 provides a summary of the authors’ reviews).
The tumor stroma (the connective and structural component of the tissue) has various cell types; however, the cancer-associated myofibroblasts (CAF) cells are one of the key cells types. The number of CAFs increase as the cancer becomes more aggressive. “It has been shown that ASCs are recruited to the tumor, transition into CAFs, and then integrate into the stroma…. The recruited ACSs can also stimulate tumor growth, promote angiogenesis, and increase cancer cell invasion. When ASCs are exposed to exosomes from breast cancer cells, they increase the expression of tumor-promoting factors…. Consequently, these ASCs promote cancer cell growth and stimulate metastasis” (p. 321-22). Additionally, these findings have been confirmed with in vivo studies.
ASCs have been demonstrated to stimulate invasion and metastasis of cancer cells; enhanced migration of several types of cancer (breast, colon, prostate, gastric, and head and neck tumors) have been shown in recent ASC studies.
Finally, there are studies demonstrating the interaction between ASCs and cancer stem cells (CSCs). As we saw earlier in this blog, EMT leads to metastasis. CSCs undergo EMT at higher frequency and metastasize into secondary organs; however, the precise and full interaction between ASCs and CSCs has yet to be discovered.
The mechanisms of ASC alterations in cancer cells and tumorigenesis varies. Table 2 outlines different cancers and different ASC alterations.
ASCs have been used as a safe and effective cellular therapy tool in the field of regenerative medicine. However, “[s]tudies have shown that ASCs isolated from obese women have an increased potential to traffic to the tumor compared to the ASCs isolated from lean women” (p. 324). Moreover, in obesity, there is an increase in the numbers of circulating ASCs and there is increased recruitment of ASCs to tumors in obesity. This is a two-fold mechanism in obesity-altered ASC tumorigenicity. Once localized into the tumor niche (microenvironment), the mobilized ASCs enhanced the tumor vasculature via transdifferentiation into perivascular cells, enhance cell survival, and limiting apoptosis (cell death) of cancer cells.
Therefore, the link between obesity and cancer is strong. Moreover, we have seen that with obesity, there are increased ASCs in circulation which supports tumors greater than ASCs from those without obesity. ASCs from obese women enhanced proliferation of breast cancer cells, express higher levels of leptin (think of previous Obesity and Stem Cell blog posts) which appears to make ASCs more effective in promoting breast cancer cell proliferation, and ASCs from obese women altered the expression of several key regulatory genes involved in cell cycles, apoptosis, angiogenesis, EMT, and metastasis. By adding additional leptin, cancer cells have increased proliferation, migration, invasion, angiogenesis, and metastasis.
The chronic, low-grade inflammation, bone marrow adipocity, Type 2 diabetes, and susceptibility to infections associated with obesity, now have another negative element…increased tumor support and protection, along with increased metastasis. While there are now data to demonstrate these dangers of obesity, more information is necessary to understand the microenvironment in greater detail as well as how obesity primes ASCs to increased tumorigenesis and metastasis. Moreover, the high metabolic demand of ASCs in obese and Type 2 diabetes patients is reminiscent to that observed in cancerous cells.(3)
Singer K, Maley N, Mergian T, et al. (2015). Differences in hematopoietic stem cells contribute to sexually dimorphic inflammatory responses to high fat diet-induced obesity. Jour of Bio Chem; 290:13250-62.
Strong AL, Burow ME, Gimble JM, and Bunnell BA. (2015). Concise Review: The Obesity Cancer Paradigm: Exploration of the interactions and cross-talk between adipose stem cells and solid tumors. Stem Cells; 33:318-26.
erena C, Keiran N, Ceperuelo-Mallafre V, et al. (2016). Obesity and Type 2 diabetes alters the immune properties of human adipose derived stem cells. Stem Cells; 34:2559-2573.