**2. Pancreas and pancreatic cancer**

#### **2.1. Pancreas: structure and function**

The pancreas functions as an accessory gland of the digestive system and is composed anatomically and functionally of a mixed, exocrine, and endocrine component. Most of the pancreatic tissue (99%) is made up of exocrine tissue that is composed of closely packed serous acini that secrete digestive enzymes (proteases, lipases, and amylases). Some of the enzymes (e.g., trypsinogen, chymotrypsinogen, and proelastase) are secreted as inactivated precursors, to prevent pancreatic cell damage, and are activated upon release in the duodenum. Other key digestive enzymes, such as α-amylase and lipase, are present in the pancreas in their active forms. The duct cells secrete a watery, bicarbonate-rich fluid that carries the enzymes and neutralizes the acidity in the small intestine. The endocrine pancreas is composed of islets of Langerhans, clusters of about 3000 cells supported by reticulin fibers, in close contact with fenestrated capillaries. They contain three types of cells that secrete the three pancreatic hormones: α cells secrete glucagon that rises the glucose blood levels, while β cells secrete insulin that decreases the glucose blood levels and Δ cells secrete somatostatin that regulates the endocrine system and affects the neurotransmission and cell proliferation. The islet cells appear paler on hematoxylin and eosin stain (**Figure 1**) [5].

#### **2.2. Pancreatic cancer**

The incidence of PC continuously raised in the past years, and it is estimated to become the second leading cause of cancer-related deaths by 2030 [6]. The highest PC incidence occurred in Northern America (7.4 per 100,000 people) and Western Europe (7.3 per 100,000 people), followed by other regions of Europe and Australia (equally about 6.5 per 100,000 people). The lowest rates (about 1.0 per 100,000 people) were observed in Middle Africa and South-Central Asia. More than half of new cases (55.5%) were registered in the more developed regions [7]. PC has been correlated to exposure to risk factors concerning lifestyle, such as obesity, or the environment [8]. The incidence of PC is higher in men than in women [9]. PC is a disease of the elderly, with most of the cases being diagnosed after the age of 55 [10]. African-Americans have the highest incidence rate of PC, that is 28-59% higher than those of other racial/ethnic groups [11].

cells. Cell nuclei often show polymorphism, hyperchromasia, loss of polarity, and proeminent nucleoli [12]. PA shows strong desmoplastic reaction that occurs around cancer cells, which is considered a hallmark for this cancer type and may account to up to 90% of the tumor volume (**Figure 2**). The stroma surrounding the cancer cells is actively involved in tumor growth and dissemination. Desmoplastic stroma is composed of extracellular matrix (ECM), cancerassociated fibroblasts, stellate and inflammatory cells, and small blood vessels. Desmoplastic stroma shows high levels of cytokines and growth factors. The desmoplastic stroma creates a barrier for chemotherapeutic drug delivery. Targeted therapies against PC stromal compo-

**Figure 2.** Representative pictures from hematoxylin and eosin staining of PC tissue. (A) Biopsy of pancreatic adenocarcinoma. The malignant glands invade tissue eliciting a strong desmoplastic reaction. Focally intraluminal mucin may be seen (10×). (B) Higher magnification of pancreatic adenocarcinoma shows malignant irregular glands composed of cell with loss of polarity, large nuclei with high nuclear-to-cytoplasmic ratio. The nuclei show irregular

**Figure 1.** Representative pictures from hematoxylin and eosin staining of pancreatic tissue. (A) Pancreatic parenchyma composed in the vast majority by the exocrine pancreas composed of tightly packed acini that secrete enzymes via a duct system in the duodenum. The endocrine pancreas is composed of islets of Langerhans, which appears as clusters of pale colored cells (10×). (B) High magnification of pancreatic tissue shows exocrine tightly packed acini and endocrine islets

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of Langerhans. The islets appear pale due to less intracytoplasmic ribosomal content (40×).

nents have so far failed to translate into significant clinical benefits [13].

shape and are hyperchromatic or vesiculated with prominent nucleoli (40×).

Most pancreatic tumors are derived from the exocrine tissue. More than 80% of the exocrine PCs are classified as pancreatic adenocarcinomas (PAs). Microscopically, these cancers are characterized by infiltrating small glands that are lined with low-columnar, mucin-containing

undergoing curative surgical treatment, the median survival remains low, around 18 months. The overall 5-year survival rate is only 8.2% for all stages of PC [2]. Despite the advances in understanding PC biology, survival rates remain unmodified in the past years [3]. The underlying causes for PC dismal prognosis, among others, are the lack of viable methods for patient screening, late detection of specific symptoms, especially in the early stages, and few targeted

The pancreas functions as an accessory gland of the digestive system and is composed anatomically and functionally of a mixed, exocrine, and endocrine component. Most of the pancreatic tissue (99%) is made up of exocrine tissue that is composed of closely packed serous acini that secrete digestive enzymes (proteases, lipases, and amylases). Some of the enzymes (e.g., trypsinogen, chymotrypsinogen, and proelastase) are secreted as inactivated precursors, to prevent pancreatic cell damage, and are activated upon release in the duodenum. Other key digestive enzymes, such as α-amylase and lipase, are present in the pancreas in their active forms. The duct cells secrete a watery, bicarbonate-rich fluid that carries the enzymes and neutralizes the acidity in the small intestine. The endocrine pancreas is composed of islets of Langerhans, clusters of about 3000 cells supported by reticulin fibers, in close contact with fenestrated capillaries. They contain three types of cells that secrete the three pancreatic hormones: α cells secrete glucagon that rises the glucose blood levels, while β cells secrete insulin that decreases the glucose blood levels and Δ cells secrete somatostatin that regulates the endocrine system and affects the neurotransmission and cell proliferation. The islet cells

The incidence of PC continuously raised in the past years, and it is estimated to become the second leading cause of cancer-related deaths by 2030 [6]. The highest PC incidence occurred in Northern America (7.4 per 100,000 people) and Western Europe (7.3 per 100,000 people), followed by other regions of Europe and Australia (equally about 6.5 per 100,000 people). The lowest rates (about 1.0 per 100,000 people) were observed in Middle Africa and South-Central Asia. More than half of new cases (55.5%) were registered in the more developed regions [7]. PC has been correlated to exposure to risk factors concerning lifestyle, such as obesity, or the environment [8]. The incidence of PC is higher in men than in women [9]. PC is a disease of the elderly, with most of the cases being diagnosed after the age of 55 [10]. African-Americans have the highest incidence rate of PC, that is 28-59% higher than those of other racial/ethnic groups [11].

Most pancreatic tumors are derived from the exocrine tissue. More than 80% of the exocrine PCs are classified as pancreatic adenocarcinomas (PAs). Microscopically, these cancers are characterized by infiltrating small glands that are lined with low-columnar, mucin-containing

therapies that remain relatively ineffective [4].

appear paler on hematoxylin and eosin stain (**Figure 1**) [5].

**2. Pancreas and pancreatic cancer**

**2.1. Pancreas: structure and function**

32 Advances in Pancreatic Cancer

**2.2. Pancreatic cancer**

**Figure 1.** Representative pictures from hematoxylin and eosin staining of pancreatic tissue. (A) Pancreatic parenchyma composed in the vast majority by the exocrine pancreas composed of tightly packed acini that secrete enzymes via a duct system in the duodenum. The endocrine pancreas is composed of islets of Langerhans, which appears as clusters of pale colored cells (10×). (B) High magnification of pancreatic tissue shows exocrine tightly packed acini and endocrine islets of Langerhans. The islets appear pale due to less intracytoplasmic ribosomal content (40×).

**Figure 2.** Representative pictures from hematoxylin and eosin staining of PC tissue. (A) Biopsy of pancreatic adenocarcinoma. The malignant glands invade tissue eliciting a strong desmoplastic reaction. Focally intraluminal mucin may be seen (10×). (B) Higher magnification of pancreatic adenocarcinoma shows malignant irregular glands composed of cell with loss of polarity, large nuclei with high nuclear-to-cytoplasmic ratio. The nuclei show irregular shape and are hyperchromatic or vesiculated with prominent nucleoli (40×).

cells. Cell nuclei often show polymorphism, hyperchromasia, loss of polarity, and proeminent nucleoli [12]. PA shows strong desmoplastic reaction that occurs around cancer cells, which is considered a hallmark for this cancer type and may account to up to 90% of the tumor volume (**Figure 2**). The stroma surrounding the cancer cells is actively involved in tumor growth and dissemination. Desmoplastic stroma is composed of extracellular matrix (ECM), cancerassociated fibroblasts, stellate and inflammatory cells, and small blood vessels. Desmoplastic stroma shows high levels of cytokines and growth factors. The desmoplastic stroma creates a barrier for chemotherapeutic drug delivery. Targeted therapies against PC stromal components have so far failed to translate into significant clinical benefits [13].

Pancreatic neuroendocrine tumors (PNETs), representing 1–2% of PC, are commonly called islet cell carcinomas. Functional PNET secretes biologically active hormones (insulin, glucagon, somatostatin, or vasoactive intestinal peptide), causing a clinical syndrome. Nonfunctioning PNET does not cause clinical symptoms [14]. Other types of exocrine PC include acinar cell carcinomas, adenosquamous carcinomas, colloid carcinomas, hepatoid carcinomas, intraductal papillary mucinous neoplasms and pancreatoblastomas [15].

The most common method for obesity detection is the determination of the body mass index (BMI) that is calculated based on the relationship between body height and weight (BMI 18.5–24.9, normal; 25.0–29.9, overweight; ≥30, obese). Obesity strongly correlates with body fat levels. Adipose tissue has a very strong endocrine function, secreting various adipokines that are involved in cancer development and progression, and insulin resistance. Leptin, IL-6, and tumor necrosis factor-alpha (TNF-α) are inflammatory factors increased in cancers, but adiponectin is protective against tumorigenesis, and its serum levels are usually decreased. Cancer patients show higher baseline levels of C-reactive protein and soluble TNFα receptor 2. Lipocalin 2 was associated with tumor invasiveness. Resistin, another proinflammatory adipokine, was increased in colon, breast, and prostate cancer. To date, many adipokines have been associated with cancer, contributing to

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enhanced inflammation, angiogenesis, cellular proliferation, and tumorigenesis [23].

One of the main adipokines is leptin, a small protein (16 kDa), which is secreted by white, brown adipose tissue and cancer cells [24]. Leptin binding to its receptor, Ob-R, in the hypothalamus controls food intake and energy expenditure. Leptin also influences the reproductive function and is a long-term regulator of body weight. Leptin is also expressed in placenta, ovaries, skeletal muscle, stomach, and mammary epithelial cells. Leptin can inhibit bone formation. It regulates the ovulatory cycle and plays an important role in embryo implantation [25]. Obese and overweight individuals have high levels of leptin in blood but exhibit leptin resistance, failing to control food intake. Leptin blood levels in obese patients are 10 times higher (40 ng/ml) than in normal individuals (4 ng/ml). The underlying mechanism of leptin resistance in obese individuals is multifactorial that includes impairment of Ob-Rb signaling, hypothalamic neuronal wiring, leptin transport into the brain and Ob-R trafficking, endoplasmic reticulum (ER) stress, and inflammation [26]. High-leptin levels can induce cancer

cell proliferation and thus can provide a link between obesity and cancer progression.

Several cancer cell types express leptin [25, 27, 28]. Both in vitro preclinical studies and patient, data suggest that leptin signaling is linked to the development of PC, breast, endometrial, colon, esophagus, stomach, thyroid gland, prostatic, hepatic, skin, brain, ovarian, lung and colon cancers, and leukemia [28–32]. Leptin can induce the development of nonalcoholic fatty liver disease, one of the major causes of hepatocellular carcinoma [33]. Leptin increases the proliferation of human myeloid leukemia cell lines and prostate cancer [34, 35]. In breast cancer, leptin increases the cancer cell proliferation and the expression of antiapoptosis-related proteins like Bcl-2 [36, 37]. Moreover, leptin induces the tumor angiogenesis, by promoting the expression of angiogenic factors, such as vascular endothelial-growth factor (VEGF) and fibroblast-growth factor 2 (FGF-2) [38]. Leptin has a direct effect on the proliferation of endothelial cells that were similar to VEGF [39]. Overall, leptin induces the production of inflammatory cytokines (IL-1, IL-6, and TNF-α), which can promote tumor invasion and metastasis [40].

There is a correlation between increased leptin levels and PC. Overexpression of leptin promotes the growth of human PC xenografts and lymph node metastasis in mice [41]. Ob-R is expressed by pancreatic cells, but its expression is increased in PC cells. Leptin binding to Ob-R induces proliferation, migration, angiogenesis and reduces PC cell apoptosis. The receptor

*3.1.1. Leptin*

The majority of PC develops silently from pancreatic intraepithelial neoplasia (PanIN) over a long period of time that highlights the importance and the challenge for early diagnosis [16]. Survival of patients with PC depends on the tumor stage at the time of diagnosis. The American Joint Committee on Cancer staging system has defined the relationship of pancreatic tumor with surrounding tissues, lymph nodes, vessels, and distant organs [17]. The first clinical stage of PC refers to tumors that are confined within the pancreas. The second stage involves PC that is spread to the adjacent tissues, especially to the lymph nodes. In Stage 3, the disease has already spread to the blood vessels, while in Stage 4, the metastasis has occurred in distant organs. Unfortunately, at the time of diagnosis, most of the patients have already invasion of vascular, lymphatic, and perineural tissue. The most common sites for distant metastasis are the liver, lung, pleura, peritoneum, and adrenal glands. Surgery may be offered to <20% of patients with PC. An additional challenge is that surgery success rate is gravely limited by the extent of early or occult micro metastases [18].
