Clear Cell Renal Cell Carcinoma Powerpoint by Krowlan5

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									Kristin Rowland
Brooks Crone
Lauren Bright
Meredith Eades
Kristen Cunningham
Carissa Chambers

Renal Cell Carcinoma

 Prevalence
   4% of all new cancer cases
   >85% of kidney cancer is RCC
     “kidney cancer” and “clear cell renal cell carcinoma” used
 Incidence increases yearly
   In both America and Industrialized Countries
     Obesity
     Stress?
     Decreased Vitamin D
        Less sunlight
            Sunscreen
            Sedentary Lifestyle
Additional Risk Factors:
   Immune Suppression
       Smoking
         >20 years had 60% increased risk compared to individuals who smoked <20 years
         Second-hand smoke shows an increased risk
       Organ Transplant
   Hereditary
       Genetics
       Gender
         Males (50-70) are most susceptible
       Hypertension
   Other predisposing factors:
       Exposure to toxic substances
         trichloroethylene
       Dialysis patients
       Obesity
         Alters hormones in body and thought to disrupt normal function of tumor
Progression of RCC

               carcinogens                        becomes
Lungs absorb                   kidneys filter                   damage to   kidney
                circulate in                    concentrated
 carcinogens                      blood                        kidney DNA   cancer
                   blood                             with

 Typically, individuals have a mutated VHL gene
   Tumor suppressor gene
 Oncogenes
   Helps normal cells become tumor cells

 Single mass in kidney
   Occasionally found in >1 area in kidney
   Can spread in both kidneys and metastasize in other
   Can be found on CT scans/ultrasounds
Role of Diet

 Fried meats increase RCC risk

 Fruit and Vegetables (especially orange/dark
  green) decrease RCC risk

 Vitamins
   Vitamin D
 Minerals
   Sodium
 Vitamin D is synthesized in the body by UVB
   90% of 1,25-dihydroxy vitamin D, the usable form, is
    obtained is from bodily synthesis by sunlight
   Reduced vitamin D intake is speculated to contribute
    to RCC.
   Linear, inverse associations between sunlight UVB
    exposure and RCC have already been made prior to
    the study by Karami et al.
   Other studies have been performed in the past
    which show that a linear, inverse relationship exists
    between RCC and UVB exposure on individuals who
    have breast, colo-rectal, ovarian, prostate, and NHL.
“Occupational Sunlight Exposure and Risk of Renal Cell Carcinoma”
     Karami S, Boffetta P, Stewart P, Rothman N, Hunting K, Dosemeci M,
     Berndt S, Brennan P, Chow W, Moore L.
1097 patients with RCC and 1476 individuals with an unrelated disease
throughout 4 countries in Eastern Europe were surveyed about their
occupation and typical workplace.
Participants were selected based on the following requirements:
     Age (20-88)
     Area of residence (lived there >1yr)
     Time between diagnosis of RCC and interview (no more than 3 months)
     Ethnicity (Caucasian).
Controls were matched based on:
     Area of residence
Occupation exposure assessment was rated on a scale categorizing
frequency, duration, confidence, and intensity of sun exposure
     Level of confidence was divided by: (<40%), probable (40-90%.) or
     certain (>90%).
     Level of intensity was categorized by “high” or low.”
For the statistical analysis of exposure categories:
   Cumulative exposure takes in all jobs, with
   emphasis on the duration in years, frequency, and
   Frequency adjusted duration takes in all jobs, but
   only uses the duration in years and frequency
   Frequency-adjusted duration for low-intensity job-
   workers only
   Frequency-adjusted duration for high-intensity
   job-workers only
   There was no overlap between exposure-
   response categories
This is the first case-controlled study which studied
occupational UV exposure and RCC risk.
Results prove that increased sunlight exposure aids
with avoiding RCC in men.
Those men who were exposed to “high” intensity levels
of sunlight showed a decreased RCC risk
    Russian men in particular show a very strong
    inverse relationship
It was not proven that UVB affects all individuals in
avoiding RCC.
Vitamin D, which is created when sunlight is on skin,
strongly influences the risk of renal cell carcinoma.
The table below highlights how the
increase in sunlight exposure significantly
reduces the risk of RCC in Russian men,
but not Russian women.
The take home message is that sunlight
exposure, which signifies Vitamin D
production, leads to a lower risk of RCC.
Therefore, with a deficient state of Vitamin
D, the risk of developing RCC is
increased. Since 90% of Vitamin D is
obtained through UVB sunlight exposure,
it can be speculated that increased
unprotected sun exposure is directly
linked to a lower risk of developing RCC.
Preventing Renal Cell Carcinoma using
             Vitamin D
             Clinical trials with many participants can easily
               cost millions of dollars. But since vitamin D is
               technically free, or super inexpensive, there is
               no reason you should be Vitamin D deficient.
             Study after study show that Vitamin D is
               apparently highly effective at preventing
               many of the health problems that big
               pharmaceutical companies have invested
               millions of dollars in developing cures.
             Vitamin D does NOT “cure” anything. None of
               these diseases are suppose to occur in the first
               place. Vitamin D simply allows our bodies to
               work the way they are designed to.
Biochemistry of Vitamin D

  Our Bodies are designed to have much more Vitamin D
circulating through them than most indoor-living westerners
                         do today.
                                            Recently, epidemiological studies
                                             suggest that Vitamin D, which is found
                                             in food (Vitamin D2 and D3) and
                                             produced in the body after exposure to
                                             UV rays from the sun (Vitamin D3) may
                                             be inversely associated with Renal Cell
                                             Carcinoma risk.
                                            Renal Cell Carcinoma (RCC) is the most
Notice the yellow (lipid/fat), the focal
                                             common malignant tumor of the
hemorrhage, and areas of necrosis
                                             kidneys. The main origin of RCC is the
**Smoking RCC patient
                                             renal proximal tubular epithelial cells
                                           RCC study
   The purpose of the study was to investigate the role of Vitamin D3 as a
    possible preventative agent against RCC.
   They measured the serum levels of Vitamin D in patients with RCC and in
    age-matched controls who were cancer-free.
   The study consisted of:
       26 women
       63 men
   Mean age: 60.8
   Controls: 54 non cancer patients with normal renal function
   RCC patients: 2 groups
       Rapid-growth type tumors (T3+T4)
       Slow-growth tumors (T1+T2)
Results of the study

 The average concentration of serum Vitamin D in
   patients with RCC was significantly lower than that in
   members of the control group.
 When the patients were divided into two groups
   depending on the speed of tumor growth, the average
   Vitamin D concentration of the slow-growth tumor group
   was significantly higher than that of rapid-growth tumor
(Refer to the White board)

 A decrease in the serum level of 1,25 (OH)2D was
  suggested to be one of the risk factors for the
  development and progression of RCC.

 The novel property of 1,25 (OH)2D3 may
  contribute to the prevention of Renal Cell
Prognostic Factors in Renal Cell Carcinoma: Association of Preoperative
Sodium Concentration with Survival
212 newly diagnosed clear cell RCC patients undergoing nephrectomy
Variables Researched:
Clinical : smoking, symptoms
Systemic: weight loss, appetite loss
Pathological: histologic subtype, tumor node metastasis (TNM) stage
Basic Lab Variables: blood count, serum sodium
Immunophenotyping: regarding antibody concentration
•Overall Survival (OS) and Disease free survival (DFS) had a median follow
up of 32 months
•Sodium concentration was considered an independently significant
predictor of both OS and DFS as well as non metastatic RCC.
   Range of serum Na+ in patients 127 to 146mmol/L
   Median Na- 139 mmol/L
   80% patients fit in 1st quartile (Q1) ≥135mmol
   Survival increased for patients with na conc above 139
    mmol/L subgroup.

 Predictors of Survival were based on SSIGN- means-
    tumor stage, size, grade, and necrosis-prognostic
    model in localized disease introduced by the Mayo

 RESULTS- showed for the first time that pre-operation
    sodium levels are an additional factor highly predictive
    of OS and RCC
 Histone Deacetylase Inhibitors Modulate Renal
   Cell Carcinoma Sensitivity to TRAIL/Apo-2L-
    Induced Apoptosis by Enhancing TRAIL-R2
 Histone deacetylases (HDAC) is one way of modification that regulates
   the level of acetylation and gene expression.
 In the progression of RCC this acetylation by HDACs increases
   proliferation of the cancerous cells.
 HDAC inhibitor (HDACI) accumulation can result in significant effects of
   inhibiting cell cycles and inducing differentiation or apoptosis of tumor
 One example of an HDACI is sodium butyrate. C4H7NaO2
 TRAIL/Apo-2L (TNF-related apoptosis-inducing ligand) is a member of the
   death receptor TNF family of cytokines. TRAIL/Apo-2L is largely non-toxic
   to normal cells but preferentially induces apoptosis in tumor cells.

 Human RCC cell lines as well as normal RPTECs (renal proximal epithelial
   cells) were used in the study.
 The cells were added to 96 well plates
 and treated for 24hrs with the TRAIL/Apo-2L
 and checked with crystal violet staining.
 The plates were then treated
  with HDACI for 16hrs prior to
  addition of TRAIL/Apo-2L.
  Each HDACIs effect was
  measured, then the TRAIL was
  added for another 5hrs.
 Cell death was determined by
  crystal violet staining and the
  analysis of apoptotic cell death
  was measured by flow

 The strain 786-O (most
  resistant ) was then put in 96
  well plates and treated in the
  presence or absence of
  different HDACIs for 16 hrs
  prior to addition of TRAIL/Apo-
 Then measured by crystal
  violet staining.
 Results:
 Sensitivity of human RCC cell lines to TRAIL/Apo-2L is enhanced following
  treatment with HDACI’s.
 Human RCC cell lines in order of sensitivity to TRAIL/Apo-2L
 A-498 ≥ ACHN > 769-P > 786-O and ≠RPTECs no sensitivity.

 TRAIL/Apo-2L and SB (or TSA) were the most potent in inducing apoptosis in RCC
    cells that were normally TRAIL/Apo-2L resistant, while at the same time had no
    effect on RPTECs.

   The reason SB was such a potent modulator to TRAIL/Apo-2L was because of its
    increased expression of the promoter TRAIL-R2. SB induces an increase in the Sp1
    levels (transcription factor) which bind readily to the multiple Sp1 binding sites of
    TRAIL-R2, thus increasing expression.
Combined HDACI, Sodium Butyrate or TSA, and TRAIL/Apo-2L
had a profound effect against proliferation of RCC cells. The
combination of HDACI (SB) and TRAIL/Apo-2L is a specific
therapy affecting only cancerous tumor cells and not affecting

Sodium acts as a modulator in as halting proliferation of
cancer cells and inducing apoptosis.
Sodium Stibogluconate

 Sodium stibogluconate (SSG) combined with
  cytokine IL-2 is proven to significantly reduce
  Renca tumors
 This statement was tested and proven from
  several experiments held by researchers from
  the Cleveland Clinic Foundation in Cleveland,
SSG study

 SSG was first tested on Renca cell growth
 They were tested in the absence and
  presence of SSG for 6 days
 There showed no decrease in growth on the
  Renca cell from either group
 This indicated that either SSG does not affect
  tumor cells at all or the SSG needs to be in
  the presence of immune cells
 Next, SSG was tested in BALB/c mice that
  had a 4-day-established Renca tumor
 SSG was daily administered for 2 weeks
 The Renca tumor decreased to 39%
  compared to 100% in the control group
  without SSG
 The results suggest that SSG has anti-tumor
 It also suggests that SSG functions through
  an indirect mechanism with anti-tumor
  immunity as opposed to a direct mechanism
  since there were no results when SSG was
  tested in the culture
 cytokine IL-2’s job is to activate
   anti-tumor immune cells such as
   T lymphocytes, Natural Killing
   cells, and tumor-infiltrating
 SSG and IL-2 combined were
   tested on Renca tumors to see if
   there was a more significant
   result than with SSG alone
 In the experiment, BALB/c mice
   bearing a 4-day-established-
   Renca tumor were treated with
   the SSG/IL-2 complex, SSG
   alone, and IL-2 alone, each for 2
 Results showed a 90% reduction
   of the tumor in mice given the
   SSG/IL-2 complex, 61%
   reduction from SSG alone, and
   no reduction with IL-2 alone.
 The researchers wondered what the mechanism
  was for the reduction of Renca tumors through
  the SSG application
 They thought SSG could possibly by increasing
  the number of anti-tumor immune cells
 They tested this hypothesis with the BALB/c
 Results indicated no increase in T or NK cells
 There was a 2 fold increase in M with SSG and a 4
  fold increase in M when SSG was combined with
 Researchers wanted to further test the significance of T cells in the SSG/IL-2
   complex even though experiments suggested there was no increase in number
 The study was done in athymic BALB/c mice lacking T cells. These mice bore a 4-
   day-established Renca tumor
 The control group was untreated while the experimental group was treated with
   the SSG/IL-2 complex
 Results indicated that the tumor continued to grow in both groups, regardless of
   the treatment
 This indicated the presence of T cells are also necessary for the SSG/IL-2 complex
   to inhibit a Renca tumor.
Clinical Correlation

There is a 52-year-old woman who presented with a history
  of hematuria and flank pain. Her symptoms started
  approximately 3 months ago. She was found to have a
  left-sided flank mass (the patient is very thin), and a CT
  scan of the abdomen revealed a suspicious 7.2-cm left-
  sided solid renal tumor.

  The remaining imaging of the abdomen, bones and brain
  were normal. CBC, metabolic panel, and LDH are all
  within normal limits. Urinalysis confirms hematuria.
 Approximately 30,000 patients in the US were
  diagnosed in 1999
   Estimated 17,800 deaths
 Arrival of incidence has risen over the past 20
  years by approximately 2 to 4% a year
 Male to female ratio is 2:1
 More common among Scandinavians and
  North Americans
 Most cases happen between 50 and 70 years
Signs and Symptoms

 Most common
   Hematuria
   Flank Pain
   Palpable mass in flank or abdomen
 Others
   Fatigue
     Night Sweats
     Malaise
     Anemia
     Hypercalcemia
     Loss of appetite
     Paraneoplastic Syndromes
Risk factors

 Cigarette Smoking
 Obesity
 Cystic kidney disease associated with chronic
  renal insufficiency
 Changes in kidney and renal dialysis
 Tuberous Sclerosis
 Hereditary renal cancer
Medical Treatment

 Surgery- generally the best option
 Chemotherapy
 Hormone therapy
 Biological therapy
   Interleukin-2 and interferon alfa (IFNa)
 Radiation Therapy

  Stop Smoking
  Healthy Diet
  Keep a healthy weight
  Routine x-rays for those on dialysis

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